The nature of the motor cortex’s intrinsic synaptic connectivity is first considered. There are two principal views on this issue. One posits that connections between cortical points are patchy, tending to link non-contiguous points of similar representation. The other posits that the nature of the connectivity is such that it binds together a variety of contiguous muscle representations acting at the same, or different, joints. The evidence for each proposition is critically examined. On the basis of methodological shortcomings and physiological considerations of the studies supporting the patchy nature of connectivity, it is concluded that the nature of the connectivity is such that it binds together heterogeneous muscle representations contiguously. It should be clear, however, that both views strongly support the idea that the motor cortex’s intrinsic synaptic connectivity is integrative in nature and that it may be the neural basis of movement-related muscle synergies. However, there is as yet no experimental evidence that supports this idea. The mechanisms of function of the motor cortex are considered next. Evidence is provided to show that single motor cortex points do not contain the circuitry necessary to produce controlled natural movements. A coordinated selection of motor cortical points is required to produce a controlled natural movement trajectory.

The effects of intracortical microstimulation (ICMS) parameters on the evoked electromyographic (EMG) responses and resulting limb movement were investigated. In ketamine-anesthetized cats, paw movement kinematics in 3D and EMG activity from 8 to 12 forelimb muscles evoked by ICMS applied to the forelimb area of the cat motor cortex (MCx) were recorded. The EMG responses evoked by ICMS were also compared to those evoked by focal ictal bursts induced by the iontophoretic ejection of the GABAA receptor antagonist bicuculline methochloride (BIC) at the same cortical point. The effects of different initial limb starting positions on movement trajectories resulting from long-duration ICMS were also studied. The ICMS duration did not affect the evoked muscle activation pattern (MAP). Short (50 ms) and long (500 ms) stimulus trains activated the same muscles in the same proportions. MAPs could, however, be modified by gradually increasing the stimulus intensity. MAPs evoked by focal ictal bursts were also highly correlated with those obtained by ICMS at the same cortical point. Varying the initial position of the forelimb did not change the MAPs evoked from a cortical point. Consequently, the evoked movements reached nearly the same final end point and posture, with variability. However, the movement trajectories were quite different depending on the initial limb configuration and starting position of the paw. The evoked movement trajectory was most natural when the forelimb lay pendant ~ perpendicular to the ground (i.e., in equilibrium with the gravitational force). From other starting positions, the movements did not appear natural. These observations demonstrate that while the output of the cortical point evokes a seemingly coordinated limb movement from a rest position, it does not specify a particular movement direction or a controlled trajectory from other initial positions.

in old age is thought to be poorer due to degeneration of the central (CNS) and peripheral nervous systems (PNS). We tested whether community-dwelling older adults (65-83 years) make larger proprioceptive errors than young adults (18-22 years) using a natural reaching task. Subjects moved the right arm to touch the index fingertip to the stationary or moving left index fingertip. The range of locations of the target index fingertip was large, sampling the natural workspace of the human arm. The target arm was moved actively by the subject or passively by the experimenter and reaching arm movements towards the target were made under visual guidance, or with vision blocked (proprioceptive guidance). Subjects did not know the direction or speed of upcoming target hand motion in the passive conditions. Mean 3D distance errors between the right and left index finger tips were small in both groups and only slightly larger when vision was blocked than when allowed, but averaged 2-5 mm larger in older than in younger adults in moving (p = 0.002) and stationary (p = 0.07) conditions, respectively. Variable errors were small and similar in the two groups (p > 0.35). Importantly, clearly larger errors were observed for reaching to the stationary than to the moving index fingertip in both groups, demonstrating that dynamic proprioceptive information during movement permits more accurate localization of the endpoint of the moving arm. This novel finding demonstrates the importance of dynamic proprioceptive information in movement guidance and bimanual coordination. (c) 2021 Published by Elsevier Ltd on behalf of IBRO.

The purpose of this study was to determine the form of the relation between the mean amplitude and variance of motor-evoked potentials (MEP). To this end, single-pulse transcranial magnetic stimulation (TMS) was applied over the motor cortex of seventeen neurologically normal adult human subjects. The coil was positioned at a locus on the scalp that elicited an MEP in the first dorsal interosseous (FDI) at the lowest stimulus intensity. The subjects were instructed to maintain tonic activity in the FDI of 5 or 10% of the maximum voluntary contraction (MVC). The relation between MEP variance and amplitude was found to have an inverted parabolic shape, with maximal variance occurring near the half-maximal MEP amplitude. The coefficient of variation $$\text{CV}$$ of MEPs decreased approximately as a rectangular hyperbolic function of MEP amplitude (i.e. ~ 1/MEP). A probabilistic model is proposed to explain the inverted parabolic relation between MEP variance and MEP amplitude, as well as the sigmoid shape of the MEP input–output relation (i.e. stimulus–response curve). The model is based on a description of α-motoneurons as binary threshold units, with unit thresholds distributed according to a positively skewed probability density function. The units are driven by noisy synaptic input currents having a Gaussian distribution. The model predicts an inverse parabolic relation between MEP variance and amplitude and a sigmoid input–output relation, as experimentally observed. Furthermore, increasing model motoneuron excitability by increasing the background synaptic drive increases MEP variability independently of MEP size, a surprising prediction. The model also explains the approximately rectangular hyperbolic relation between $$\text{CV}$$ and MEP amplitude. The implications of these results for the interpretation of neurophysiological experiments and the statistical analysis of MEPs are discussed.

We can easily and without sight bring our fingertip to our nose, or swat a mosquito on our arm. These actions rely on proprioception, also known as kinesthesia, which classically has been attributed to processing of sensory inflow by the CNS. However, internal model theories of sensorimotor neuroscience propose that proprioceptive localization also involves a contribution from estimates of limb kinematics derived from motor commands. We tested this prediction in 19 subjects who moved the right index finger tip to touch the moving left index finger tip under three conditions: (1) vision allowed, active movement of the left hand (2) vision blocked, active movement of the left hand, and (3) vision blocked, passive movement of the left hand imposed by the experimenter. The target left index finger tip was moved in a wide range of directions by unrestricted movements of the arm. Mean errors in apposition of the right to the left index finger tips were small, averaging <2 cm between sensors fixed to the finger nails. Note that the average distance between the sensors was ~1.7 cm when the fingertips were brought together in “perfect” apposition under visual guidance. The 3D mean distance and variable distance errors were marginally lower by some 2 mm with eyes open compared to the eyes closed active condition. However, mean distance and variable distance errors did not differ between the active and passive conditions with eyes closed. Thus, proprioceptive localization of one's moving hand is very accurate, essentially as accurate as when vision is allowed. More importantly, our results demonstrate that hypothesized internal model derived estimates of arm kinematics do not contribute to localization accuracy beyond that provided by sensory signals, casting doubt on their existence.

Nature has solved the problem of controlling legged locomotion many thousands of times in animals exhibiting an enormous variety of neuromechanical structures. Control systems features that are common to nearly all species include feedback control of limb displacement and force and feedforward generation of motor patterns by neural networks within the central nervous system (Central Pattern Generators: CPGs). Here we review the components of locomotor control systems, with a focus on mammalian animals including humans. We then propose a generalized model of reflex control and discuss the mathematical functions that describe the properties of the components of a spinal stretch reflex model. Reflex model of neuromuscular control. Here we provide and discuss the mathematical functions for the components in the reflex model presented in Subchapter 6.6. These include functions that describe muscle intrinsic properties (excitation–contraction coupling, force–velocity and orce–length curves) and sensory receptor models (muscle spindle responses to length changes and fusimotor drive, Golgi tendon organ responses to changes in muscle force).

Experiments were done to determine whether the starting position of the arm influences its final configuration (posture) when pointing to, or grasping, targets located within the common workspace of the arm. Subjects were asked to point to, or grasp, each of six targets from five, or seven, widely spaced starting positions. We found that the variability (standard deviation) of the arm's configuration, measured as the angle of inclination of the plane delimited by the arm and forearm, averaged about 4° for comfortable speed pointing movements and was only slightly higher for fast pointing movements. Comfortable speed reaches to grasp the targets were associated with slightly lower variability (3.5°) in final arm configuration. The average variability of repeated movements to a given target from a single start position (3.5°) was comparable to that of movements from different start positions to the same target (4.2°). A small difference in final arm inclination angle, averaged across all subjects and targets, of 3° was found between two pairs of starting positions. This small and possibly idiosyncratic effect is within the "noise" of final arm orientation variability for repeated movements (i.e., 3.5°). Thus, the variability of final posture is not for the most part due to different start positions, it is inherent to movement per se. Our results reconcile conflicting previous studies and are consistent with past works suggesting that a Donders' like law is indeed largely upheld for unconstrained visually guided arm movements. In summary, considering movements within a typical work space, when the hand is moved voluntarily to a given spatial location the posture of the arm is nearly the same regardless of its starting position. Importantly, variability is inherent to the rule.

Given the non-linearities of the neural circuitry's elements, we would expect cortical circuits to respond non-linearly when activated. Surprisingly, when two points in the motor cortex are activated simultaneously, the EMG responses are the linear sum of the responses evoked by each of the points activated separately. Additionally, the corticospinal transfer function is close to linear, implying that the synaptic interactions in motor cortex must be effectively linear. To account for this, here we develop a model of motor cortex composed of multiple interconnected points, each comprised of reciprocally connected excitatory and inhibitory neurons. We show how non-linearities in neuronal transfer functions are eschewed by strong synaptic interactions within each point. Consequently, the simultaneous activation of multiple points results in a linear summation of their respective outputs. We also consider the effects of reduction of inhibition at a cortical point when one or more surrounding points are active. The network response in this condition is linear over an approximately two- to three-fold decrease of inhibitory feedback strength. This result supports the idea that focal disinhibition allows linear coupling of motor cortical points to generate movement related muscle activation patterns; albeit with a limitation on gain control. The model also explains why neural activity does not spread as far out as the axonal connectivity allows, whilst also explaining why distant cortical points can be, nonetheless, functionally coupled by focal disinhibition. Finally, we discuss the advantages that linear interactions at the cortical level afford to motor command synthesis.

Recent studies on the functional organization and operational principles of the motor cortex (MCx), taken together, strongly support the notion that the MCx controls the muscle synergies subserving movements in an integrated manner. For example, during pointing the shoulder, elbow and wrist muscles appear to be controlled as a coupled functional system, rather than singly and separately. The recurrent pattern of intrinsic synaptic connections between motor cortical points is likely part of the explanation for this operational principle. So too is the reduplicated, non-contiguous and intermingled representation of muscles in the MCx. A key question addressed in this article is whether the selection of movement related muscle synergies is a dynamic process involving the moment to moment functional linking of a variety of motor cortical points, or rather the selection of fixed patterns embedded in the MCx circuitry. It will be suggested that both operational principles are probably involved. We also discuss the neural mechanisms by which cortical points may be dynamically linked to synthesize movement related muscle synergies. Separate corticospinal outputs sum linearly and lead to a blending of the movements evoked by activation of each point on its own. This operational principle may simplify the synthesis of motor commands. We will discuss two possible mechanisms that may explain linear summation of outputs. We have observed that the final posture of the arm when pointing to a given spatial location is relatively independent of its starting posture. From this observation and the recurrent nature of the MCx intrinsic connectivity we hypothesize that the basic mode of operation of the MCx is to associate spatial location to final arm posture. We explain how the recurrent network connectivity operates to generate the muscle activation patterns (synergies) required to move the arm and hold it in its final position.

We re-examined the issue of active versus passive proprioception to more fully characterize the accuracy afforded by proprioceptive information in natural, unconstrained, movements in 3-dimensions. Subjects made pointing movements with their non-dominant arm to various locations with eyes closed. They then proprioceptively localized the tip of its index finger with a prompt pointing movement of their dominant arm, thereby bringing the two indices in apposition. Subjects performed this task with remarkable accuracy. More remarkably, the same subjects were equally accurate at localizing the index finger when the arm was passively moved and maintained in its final position by an experimenter. Two subjects were also tested with eyes open, and they were no more accurate than with eyes closed. We also found that the magnitude of the error did not depend on movement duration, which is contrary to a key observation in support of the existence of an internal forward model-based state-reconstruction scheme. Three principal conclusions derive from this study. First, in unconstrained movements, proprioceptive information provides highly accurate estimates of limb position. Second, so-called active proprioception does not provide better estimates of limb position than passive proprioception. Lastly, in the active movement condition, an internal model-based estimation of limb position should, according to that hypothesis, have occurred throughout the movement. If so, it did not lead to a better estimate of final limb position, or lower variance of the estimate, casting doubt on the necessity to invoke this hypothetical construct.

Motor cortical points are linked by intrinsic horizontal connections having a recurrent network topology. However, it is not known whether neural activity can propagate over the area covered by these intrinsic connections and whether there are spatial anisotropies of synaptic strength, as opposed to synaptic density. Moreover, the mechanisms by which activity spreads have yet to be determined. To address these issues, an 8 × 8 microelectrode array was inserted in the forelimb area of the cat motor cortex (MCx). The centre of the array had a laser etched hole ∼500 μm in diameter. A microiontophoretic pipette, with a tip diameter of 2-3 μm, containing bicuculline methiodide (BIC) was inserted in the hole and driven to a depth of 1200-1400 μm from the cortical surface. BIC was ejected for ∼2min from the tip of the micropipette with positive direct current ranging between 20 and 40 nA in different experiments. This produced spontaneous nearly periodic bursts (0.2-1.0 Hz) of multi-unit activity in a radius of about 400 μm from the tip of the micropipette. The bursts of neural activity spread at a velocity of 0.11-0.24 ms⁻¹ (mean=0.14 mm ms⁻¹, SD=0.05)with decreasing amplitude.The area activated was on average 7.22 mm² (SD=0.91 mm²), or ∼92% of the area covered by the recording array. The mode of propagation was determined to occur by progressive recruitment of cortical territory, driven by a central locus of activity of some 400 μm in radius. Thus, activity did not propagate as a wave. Transection of the connections between the thalamus and MCx did not significantly alter the propagation velocity or the size of the recruited area, demonstrating that the bursts spread along the routes of intrinsic cortical connectivity. These experiments demonstrate that neural activity initiated within a small motor cortical locus (≤ 400 μm in radius) can recruit a relatively large neighbourhood in which a variety of muscles acting at several forelimb joints are represented. These results support the hypothesis that the MCx controls the forelimb musculature in an integrated and anticipatory manner based on a recurrent network topology

The purpose of this study was to determine whether task-dependent differences in corticospinal pathway excitability occur in going from isolated contractions of the index finger to its coordinated activity with the thumb. Focal transcranial magnetic stimulation (TMS) was used to measure input-output (I/O) curves--a measure of corticospinal pathway excitability--of the contralateral first dorsal interosseus (FDI) muscle in 21 healthy subjects performing two isometric motor tasks: index abduction and precision grip. The level of FDI electromyographic (EMG) activity was kept constant across tasks. The amplitude of the FDI motor evoked potentials (MEPs) and the duration of FDI silent period (SP) were plotted against TMS stimulus intensity and fitted, respectively, to a Boltzmann sigmoidal function. The plateau level of the FDI MEP amplitude I/O curve increased by an average of 40% during the precision grip compared with index abduction. Likewise, the steepness of the curve, as measured by the value of the maximum slope, increased by nearly 70%. By contrast, all I/O curve parameters [plateau, stimulus intensity required to obtain 50% of maximum response (S(50)), and slope] of SP duration were similar between the two tasks. Short- and long-latency intracortical inhibitions (SICI and LICI, respectively) were also measured in each task. Both measures of inhibition decreased during precision grip compared with the isolated contraction. The results demonstrate that the motor cortical circuits controlling index and thumb muscles become functionally coupled when the muscles are used synergistically and this may be due, at least in part, to a decrease of intracortical inhibition and an increase of recurrent excitation.

The details and functional significance of the intrinsic horizontal connections between neurons in the motor cortex (MCx) remain to be clarified. To further elucidate the nature of this intracortical connectivity pattern, experiments were done on the MCx of three cats. The anterograde tracer biocytin was ejected iontophoretically in layers II, III, and V. Some 30-50 neurons within a radius of approximately 250 microm were thus stained. The functional output of the motor cortical point at which biocytin was injected, and of the surrounding points, was identified by microstimulation and electromyographic recordings. The axonal arborizations of the stained neurons were traced under camera lucida. The axon collaterals were extensive, reaching distances of <or=7 mm from the injection site. More importantly, the axonal branches were studded all along their course with boutons. The vast majority of boutons formed synaptic contacts on the target cells as identified by electron microscopy. The majority of these boutons made asymmetric (type I, excitatory) synapses mainly on dendritic spines. The bouton density decreased approximately monotonically with distance from the center of the injection. Cluster analysis, lagged covariance analysis, and eigenvalue decomposition showed the bouton distribution map to be unimodal. Superposition of the synaptic bouton distribution map and the motor output map revealed that motor cortical neurons don't make point-to-point connections but rather bind together the representations of a variety of muscles within a large neighborhood. This recurrent-network type connectivity strongly supports the hypothesis that the MCx controls the musculature in an integrated manner.

We recently suggested that movement-related inter-joint muscle synergies are recruited by selected excitation and selected release from inhibition of cortical points. Here we asked whether a similar cortical mechanism operates in the functional linking of antagonistic muscles. To this end experiments were done on ketamine-anesthetized cats. Intracortical microstimulation (ICMS) and intramuscular electromyographic recordings were used to find and characterize wrist, elbow and shoulder antagonistic motor cortical points. Simultaneous ICMS applied at two cortical points, each evoking activity in one of a pair of antagonistic muscles, produced co-contraction of antagonistic muscle pairs. However, we found an obvious asymmetry in the strength of reciprocal inhibition; it was always significantly stronger on physiological extensors than flexors. Following intravenous injection of a single bolus of strychnine, a cortical point at which only a physiological flexor was previously activated also elicited simultaneous activation of its antagonist. This demonstrates that antagonistic corticospinal neurons are closely grouped, or intermingled. To test whether releasing a cortical point from inhibition allows it to be functionally linked with an antagonistic cortical point, one of three GABA(A) receptor antagonists, bicuculline, gabazine or picrotoxin, was injected iontophoretically at one cortical point while stimulation was applied to an antagonistic cortical point. This coupling always resulted in co-contraction of the represented antagonistic muscles. Thus, antagonistic motor cortical points are linked by excitatory intracortical connections held in check by local GABAergic inhibition, with reciprocal inhibition occurring at the spinal level. Importantly, the asymmetry of cortically mediated reciprocal inhibition would appear significantly to bias muscle maps obtained by ICMS in favor of physiological flexors.

The purpose of this study was to determine the relative size and location of proximal and distal upper limb muscle representations in the human motor cortex. Motor-evoked potentials (MEPs) evoked by transcranial magnetic stimulation were recorded in the proximal muscle anterior deltoid (AD) and in the distal muscles extensor carpi radialis (ECR) and first dorsal interosseus (1DI). The coil was moved in steps of 1 cm along a grid drawn on a tight-fitting polyester cap placed on the subject's head. At each location, four stimuli were delivered at 1.2 times the active motor threshold (AMT), and MEPs averaged in real-time. The peak-to-peak amplitude of each muscle's mean MEP was measured at each stimulation site. The area of a muscle's representation was measured by a pixel-counting algorithm. The optimal point of each muscle's areal representation, which corresponds to the locus near which the largest MEPs are obtained, was determined by fitting a 3D Lorentzian function to the data points. The optimal point of distal muscles tended to be situated more laterally along the motor strip than that of proximal muscles. However, there was no statistically significant difference between the size of the areal representations and they overlapped considerably. Additionally, in another five subjects, using a small 45-mm coil placed in a hyper-focal orientation, maps were obtained at a stimulus intensity of 1.1-1.15 times the AMT of the muscle with the lowest threshold, usually the 1DI. Even in this very stringent condition, the mapped representations of the AD, ECR and 1DI overlapped, notwithstanding that sharp demarcations between borders were also apparent. These observations demonstrate that stimulus spread alone does not explain the overlap of muscle representations. These results show that commonly used proximal and distal upper-limb muscles, taken individually, are controlled by motor cortical territories of approximately equal size that significantly overlap despite differences in the location of their optimal points.

Recruitment of movement-related muscle synergies involves the functional linking of motor cortical points. We asked how the outputs of two simultaneously stimulated motor cortical points would interact. To this end, experiments were done in ketamine-anesthetized cats. When prolonged (e.g., 500 ms) trains of intracortical microstimulation were applied in the primary motor cortex, stimulus currents as low as 10-20 microA evoked coordinated movements of the contralateral forelimb. Paw kinematics in three dimensions and the electromyographic (EMG) activity of eight muscles were simultaneously recorded. We show that the EMG outputs of two cortical points simultaneously stimulated are additive. The movements were represented as displacement vectors pointing from initial to final paw position. The displacement vectors resulting from simultaneous stimulation of two cortical points pointed in nearly the same direction as the algebraic resultant vector. Linear summation of outputs was also found when inhibition at one of the cortical points was reduced by GABAA receptor antagonists. A simple principle emerges from these results. Notwithstanding the underlying complex neuronal circuitry, motor cortex outputs combine nearly linearly in terms of movement direction and muscle activation patterns. Importantly, simultaneous activation does not change the nature of the output at each point. An additional implication is that not all possible movements need be explicitly represented in the motor cortex; a large number of different movements may be synthesized from a smaller repertoire.