Complementary roles of primate dorsal premotor and pre-supplementary motor areas to the control of motor sequences.

We are able to temporally organize multiple movements in a purposeful manner in everyday life. Both the dorsal premotor (PMd) and pre-supplementary motor areas (pre-SMA) are known to be involved in the performance of motor sequences. However, it is unclear how each area differentially contributes to controlling multiple motor sequences. To address this issue, we recorded single-unit activity in both areas while monkeys (one male, one female) performed sixteen motor sequences. Each sequence comprised either a series of two identical movements (repetitive) or two different movements (non-repetitive). The sequence was initially instructed with visual signals but had to be remembered thereafter. Here we showed that the activity of single neurons in both areas transitioned from reactive- to predictive encoding while motor sequences were memorized. In the memory-guided trials, in particular, the activity of PMd cells preferentially represented the second movement in the sequence leading to a reward generally irrespective of the first movement. Such activity frequently began even before the first movement in a prospective manner, and was enhanced in non-repetitive sequences. Behaviorally, a lack of the activity enhancement often resulted in premature execution of the second movement. In contrast, cells in pre-SMA instantiated particular sequences of actions by coordinating switching or non-switching movements in sequence. Our findings suggest that PMd and pre-SMA play complementary roles within behavioral contexts: PMd preferentially controls the movement that leads to a reward rather than the sequence per se, whereas pre-SMA coordinates all elements in a sequence by integrating temporal orders of multiple movements.Significance statement:Although both PMd and pre-SMA are involved in the control of motor sequences, it is not clear how these two areas contribute to coordination of sequential movements differently. To address this issue, we directly compared neuronal activity in the two areas recorded while monkeys memorized and performed multiple motor sequences. Our findings suggest that PMd preferentially represents the final action that ultimately leads to a reward in a prospective manner, whereas the pre-SMA coordinates switching among multiple actions within the context of the sequence. Our findings are of significance to understand the distinct roles for motor-related areas in the planning and executing motor sequences and the pathophysiology of apraxia and/or Parkinson's diseases that disables skilled motor actions.

A secondary motor area contributing to interlimb coordination during visually guided locomotion in the cat.

We investigated the contribution of cytoarchitectonic cortical area 4δc, in the caudal bank of the cruciate sulcus of the cat, to the control of visually guided locomotion. To do so, we recorded the activity of 114 neurons in 4δc while cats walked on a treadmill and stepped over an obstacle that advanced toward them. A total of 84/114 (74%) cells were task-related and 68/84 (81%) of these cells showed significant modulation of their discharge frequency when the contralateral limbs were the first to step over the obstacle. These latter cells included a substantial proportion (27/68 40%) that discharged between the passage of the contralateral forelimb and the contralateral hindlimb over the obstacle, suggesting a contribution of this area to interlimb coordination. We further compared the discharge in area 4δc with the activity patterns of cells in the rostral division of the same cytoarchitectonic area (4δr), which has been suggested to be a separate functional region. Despite some differences in the patterns of activity in the 2 subdivisions, we suggest that activity in each is compatible with a contribution to interlimb coordination and that they should be considered as a single functional area that contributes to both forelimb-forelimb and forelimb-hindlimb coordination.

Microstimulation of the Premotor Cortex of the Cat Produces Phase-Dependent Changes in Locomotor Activity.

To determine the functional organization of premotor areas in the cat pericruciate cortex we applied intracortical microstimulation (ICMS) within multiple cytoarchitectonically identified subregions of areas 4 and 6 in the awake cat, both at rest and during treadmill walking. ICMS in most premotor areas evoked clear twitch responses in the limbs and/or head at rest. During locomotion, these same areas produced phase-dependent modifications of muscle activity. ICMS in the primary motor cortex (area 4γ) produced large phase-dependent responses, mostly restricted to the contralateral forelimb or hindlimb. Stimulation in premotor areas also produced phase-dependent responses that, in some cases, were as large as those evoked from area 4γ. However, responses from premotor areas had more widespread effects on multiple limbs, including the ipsilateral limbs, than did stimulation in 4γ. During locomotion, responses in both forelimb and hindlimb muscles were evoked from cytoarchitectonic areas 4γ, 4δ, 6aα, and 6aγ. However, the prevalence of effects in a given limb varied from one area to another. The results suggest that premotor areas may contribute to the production, modification, and coordination of activity in the limbs during locomotion and may be particularly pertinent during modifications of gait.

Premotor Cortex Provides a Substrate for the Temporal Transformation of Information During the Planning of Gait Modifications.

We tested the hypothesis that the premotor cortex (PMC) in the cat contributes to the planning and execution of visually guided gait modifications. We analyzed single unit activity from 136 cells localized within layer V of cytoarchitectonic areas 6iffu and that part of 4δ within the ventral bank of the cruciate sulcus while cats walked on a treadmill and stepped over an obstacle that advanced toward them. We found a rich variety of discharge patterns, ranging from limb-independent cells that discharged several steps in front of the obstacle to step-related cells that discharged either during steps over the obstacle or in the steps leading up to that step. We propose that this population of task-related cells within this region of the PMC contributes to the temporal evolution of a planning process that transforms global information of the presence of an obstacle into the precise spatio-temporal limb adjustment required to negotiate that obstacle.

Intended arm use influences interhemispheric correlation of ß-oscillations in primate medial motor areas.

To investigate the role of interhemispheric ß-synchronization in the selection of motor effectors, we trained two monkeys to memorize and perform multiple two-movement sequences that included unimanual repetition and bimanual switching. We recorded local field potentials simultaneously in the bilateral supplementary motor area (SMA) and pre-SMA to examine how the ß-power in both hemispheres and the interhemispheric relationship of ß-oscillations depend on the prepared sequence of arm use. We found a significant ipsilateral enhancement of ß-power for bimanual switching trials in the left hemisphere and an enhancement of ß-power in the right SMA while preparing for unimanual repetition. Furthermore, interhemispheric synchrony in the SMA was significantly more enhanced while preparing unimanual repetition than while preparing bimanual switching. This enhancement of synchrony was detected in terms of ß-phase but not in terms of modulation of ß-power. Furthermore, the assessment of the interhemispheric phase difference revealed that the ß-oscillation in the hemisphere contralateral to the instructed arm use significantly advanced its phase relative to that in the ipsilateral hemisphere. There was no arm use-dependent shift in phase difference in the pairwise recordings within each hemisphere. Both neurons with and without arm use-selective activity were phase-locked to the ß-oscillation. These results imply that the degree of interhemispheric phase synchronization as well as phase differences and oscillatory power in the ß-band may contribute to the selection of arm use depending on the behavioral conditions of sequential arm use.NEW & NOTEWORTHY We addressed interhemispheric relationships of ß-oscillations during bimanual coordination. While monkeys prepared to initiate movement of the instructed arm, ß-oscillations in the contralateral hemisphere showed a phase advance relative to the other hemisphere. Furthermore, the sequence of arm use influenced ß-power and the degree of interhemispheric phase synchronization. Thus the dynamics of interhemispheric phases and power in ß-oscillations may contribute to the specification of motor effectors in a given behavioral context.

The Suppression of Beta Oscillations in the Primate Supplementary Motor Complex Reflects a Volatile State During the Updating of Action Sequences.

The medial motor areas play crucial but flexible roles in the temporal organizations of multiple movements. The beta oscillation of local field potentials is the predominant oscillatory activity in the motor areas, but the manner in which increases and decreases in beta power contribute to updating of multiple action plans is not yet fully understood. In the present study, beta and high-gamma activities in the supplementary motor area (SMA) and pre-SMA of monkeys were analyzed during performance of a bimanual motor sequence task that required updating and maintenance of the memory of action sequences. Beta power was attenuated during early delay periods of updating trials but was increased during maintenance trials, while there was a reciprocal increase in high-gamma power during updating trials. Moreover, transient attenuation of beta power during maintenance trials resulted in the erroneous selection of an action sequence. Therefore, it was concluded that the suppression of beta power during the early delay period reflects volatility of neural representation of the action sequence. This neural representation would be properly updated to the appropriate instructed action sequence via increases in high-gamma power in updating trials whereas it would be erroneously updated without the appropriate updating signal in maintenance trials.

Two-dimensional representation of action and arm-use sequences in the presupplementary and supplementary motor areas.

The medial frontal cortex has been thought to be crucially involved in temporal structuring of behavior in monkeys and humans. We examined neuronal activity in the supplementary and presupplementary motor areas of monkeys to investigate how the nervous system deals with the coding of 16 motor sequences resulting from multiple actions involving bilateral use of the arms. We first found in both areas that this behavioral demand resulted in attribute-based representation of individual motor acts, reflecting functional (action) or anatomical (right/left arm) attributes. Actions were frequently represented according to a body-axis-centered reference frame (supination or pronation) regardless of the arm to be used. Moreover, behavioral sequences were primarily represented with respect to the action- or arm-use sequence rather than the sequence of individual movements. We propose that the two-dimensional attribute-based sequence representation provides a robust and efficient means of processing multiple behavioral sequences.

Exploring the Consistent Roles of Motor Areas Across Voluntary Movement and Locomotion.

Multiple cortical motor areas are critically involved in the voluntary control of discrete movement (e.g., reaching) and gait. Here, we outline experimental findings in nonhuman primates with clinical reports and research in humans that explain characteristic movement control mechanisms in the primary, supplementary, and presupplementary motor areas, as well as in the dorsal premotor area. We then focus on single-neuron activity recorded while monkeys performed motor sequences consisting of multiple discrete movements, and we consider how area-specific control mechanisms may contribute to the performance of complex movements. Following this, we explore the motor areas in cats that we have considered as analogs of those in primates based on similarities in their cortical surface topology, anatomic connections, microstimulation effects, and activity patterns. Emphasizing that discrete movement and gait modification entail similar control mechanisms, we argue that single-neuron activity in each area of the cat during gait modification is compatible with the function ascribed to the activity in the corresponding area in primates, recorded during the performance of discrete movements. The findings that demonstrate the premotor areas' contribution to locomotion, currently unique to the cat model, should offer highly valuable insights into the control mechanisms of locomotion in primates, including humans.

Wireless system for recording evoked potentials.

Experiments measuring evoked potentials require flexible and rapid adjustment of stimulation and recording parameters. In this study, we have developed a recording system and an associated Android application that allow making such adjustments wirelessly. The system consists of 3 units: for stimulation, recording and control. Most of the modules in this system are custom made, although the stimulator and tablet are off-the-shelf products. When installed on the tablet, our Android application allows wireless communication with the control unit from a distance of 5 m. In testing, the recording unit had low internal noise and displayed signals faithfully. Upon receiving commands from the control unit, the stimulation unit produced precisely timed pulse outputs. Using this system, we were able to record evoked field potentials in the dentate gyrus of a rat; responses increased as expected with increasing stimulation pulse amplitude and duration.

Cortical contribution to visuomotor coordination in locomotion and reaching.

One of the hallmarks of mammals is their ability to make precise visually guided limb movements to attain objects. This is best exemplified by the reach and grasp movements of primates, although it is not unique to this mammalian order. Precise, coordinated, visually guided movements are equally as important during locomotion in many mammalian species, especially in predators. In this context, vision is used to guide paw trajectory and placement. In this review we examine the contribution of the fronto-parietal network in the control of such movements. We suggest that this network is responsible for visuomotor coordination across behaviours and species. We further argue for analogies between cytoarchitectonically similar cortical areas in primates and cats.

[Cortical Control of Steps During Locomotion to Avoid Obstacles].

Although it has long been known that cortical contribution is undoubtedly necessary for visually guided modification of steps during locomotion, most of the physiological evidence for cortical contribution has been accumulated since the 1980s. This article reviews evidence obtained from experiments on cats that have demonstrated the involvement of the primary motor cortex (MI), posterior parietal cortex (PPC), and premotor areas (PM) in visually guided locomotion. Activity in the MI, which is tightly coupled with muscle activity of the contralateral limbs, has been thought to control muscle synergy of contralateral limbs through spinal interneurons to modify steps. Signals from the PPC are often effector-independent; this area signals spatiotemporal relationships between an obstacle and the body. Activity in the PM is more effector-specific than that in the PPC; the PM seems to receive the spatiotemporal information from the PPC and transform it to effector-specific signals that allow the MI to send commands to modify steps taken by the contralateral limbs. These findings support the view that network activity between the PPC and PM is necessary for controlling not only segmental movements such as reaching with one arm, but also visually guided locomotion.

Theta Dynamics Contribute to Retrieving Motor Plans after Interruptions in the Primate Premotor Area.

To achieve a behavioral goal, we often need to maintain an internal action plan against external interruption and thereafter retrieve the action plan. We recently found that the maintenance and updating of motor plans are reflected by reciprocal changes in the beta and gamma power of the local field potential (LFP) of the primate medial motor areas. In particular, the maintenance of the immediate motor plan is supported by enhanced beta oscillations. However, it is unclear how the brain manages to maintain and retrieve the internal action plan against interruptions. Here, we show that dynamic theta changes contribute to the maintenance of the action plan. Specifically, the power of the theta frequency band (4-10 Hz) of LFPs increased before and during the interruption in the dorsal premotor areas in two monkeys. Without theta enhancement before the interruption, retrieval of the internal action plan was impaired. Theta and beta oscillations showed distinct changes depending on the behavioral context. Our results demonstrate that immediate and suspended motor plans are supported by the beta and theta oscillatory components of LFPs. Motor cortical theta oscillations may contribute to bridging motor plans across behavioral interruptions in a prospective manner.

Preceding Postural Control in Forelimb Reaching Movements in Cats.

Postural control precedes the goal-directed movement to maintain body equilibrium during the action. Because the environment continuously changes due to one's activity, postural control requires a higher-order brain function that predicts the interaction between the body and the environment. Here, we tried to elucidate to what extent such a preceding postural control (PPC) predictively offered a posture that ensured the entire process of the goal-directed movement before starting the action. For this purpose, we employed three cats, which we trained to maintain a four-leg standing posture on force transducers to reach the target by either forelimb. Each cat performed the task under nine target locations in front with different directions and distances. As an index of posture, we employed the center of pressure (CVP) and examined CVP positions when the cat started postural alteration, began to lift its paw, and reached the target. After gazing at the target, each cat started PPC where postural alteration was accompanied by a 20-35 mm CVP shift to the opposite side of the forelimb to be lifted. Then, the cat lifted its paw at the predicted CVP position and reached the forelimb to the target with a CVP shift of only several mm. Moreover, each cat had an optimal target location where the relationship between the cat and target minimized the difference in the CVP positions between the predicted and the final. In this condition, more than 80% of the predicted CVP positions matched the final CVP positions, and the time requiring the reaching movement was the shortest. By contrast, the forelimb reaching movement required a greater CVP shift and longer time when the target was far from the cat. In addition, the time during forelimb reaching showed a negative correlation with the speed of the CVP shift during the PPC. These results suggest that the visuospatial information, such as the body-environment interaction, contributes to the motor programming of the PPC. We conclude that the PPC ensures postural stability throughout the action to optimize the subsequent goal-directed movements. Impairments in these processes may disturb postural stability during movements, resulting in falling.

Decoding higher-order motor information from primate non-primary motor cortices.

To investigate the involvement of primate non-primary motor cortices in bimanual sequential movements, we recorded neuronal activity in the supplementary motor area (SMA) and presupplementary motor area (pre-SMA) while an animal was performing bimanual motor tasks that required two sequential arm movements consisting of either pronation or supination of the right or left arms with delay periods. We also recorded electromyograms (EMGs) from the arm while the animal performed the bimanual task to compare muscle and neuronal activity. This paper focuses on the neuronal activity before the onset of sequential movements. We found that the prime-mover forelimb muscles were selectively active when an impending arm movement involved recorded muscles, but was not dependent on whether the arm movements were bimanual or unimanual. In contrast, we found that neurons in the non-primary motor cortices showed different activity depending on whether the forthcoming sequential arm movements were unimanual or bimanual. Our results suggest that neuronal activity in the SMA and pre-SMA reflects higher-order information about arm use before motor execution. By extracting this type of information, we can use it to control prosthetic arms in a more intelligent manner through a brain-machine interface.

Arm-use dependent lateralization of gamma and beta oscillations in primate medial motor areas.

The neurons in the motor cortex show lateralization depending on the arm to use. To investigate if local field potential (LFP) oscillations change with contralateral and ipsilateral arm use, we analyzed the power of LFP in supplementary motor areas (SMA) and pre-SMA while animals performed a delayed-response arm use task under visual guidance and memory-based. LFP power changed with the laterality of the arm use, but it was frequency dependent. Specifically, power in the gamma range increased during contralateral arm use, while beta power increased with ipsilateral arm use. Subsequently, we confirmed that the frequency-dependent laterality was true also for the memory-driven movements. Our data therefore suggest that gamma oscillation is linked to the local neuronal activities in the contralateral hemisphere, and beta oscillation is related to withholding undesired arm movements by suppression of the local neuronal activities of the ipsilateral hemisphere.

Covert representation of second-next movement in the pre-supplementary motor area of monkeys.

We attempted to analyze the nature of premovement activity of neurons in medial motor areas [supplementary motor area (SMA) and pre-SMA] from a perspective of coding multiple movements. Monkeys were trained to perform a series of two movements with an intervening delay: supination or pronation with either forearm. Movements were initially instructed with visual signals but had to be remembered thereafter. Although a well-known type of premovement activity representing the forthcoming movements was found in the two areas, we found an unexpected type of activity that represented a second-next movement before initiating the first of the two movements. Typically in the pre-SMA, such activity selective for the second-next movement peaked before the initiation of the first movement, decayed thereafter, and remained low in magnitude while initiating the second movement. This type of activity may tentatively hold information for the second movement while initiating the first. That information may be fed into another group of neurons that themselves build a preparatory activity required to plan the second movements. Alternatively, the activity could serve as a signal to inhibit a premature exertion of the motor command for the second movement.