Orwik

On the nature of the intrinsic connectivity of the cat motor cortex: evidence for a recurrent neural network topology.

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... expand abstract 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 collapse abstract

Corticospinal control of antagonistic muscles in the cat.

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 linki... expand abstractng 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. collapse abstract

Linear summation of cat motor cortex outputs.

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-... expand abstractanesthetized 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. collapse abstract

The comparable size and overlapping nature of upper limb distal and proximal muscle representations in the human motor cortex.

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 ... expand abstractthe 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. collapse abstract

On the potential role of the corticospinal tract in the control and progressive adaptation of the soleus h-reflex during backward walking.

When untrained subjects walk backward on a treadmill, an unexpectedly large amplitude soleus H-reflex occurs in the midswing phase of backward walking. We hypothesized that activity in the corticospinal tract (CST) during midswing depolarizes the sol... expand abstracteus alpha-motoneurons subliminally and thus brings them closer to threshold. To test this hypothesis, transcranial magnetic stimulation (TMS) was applied to the leg area of the motor cortex (MCx) during backward walking. Motor-evoked potentials (MEPs) were recorded from the soleus and tibialis anterior (TA) muscles in untrained subjects at different phases of the backward walking cycle. We reasoned that if soleus MEPs could be elicited in midswing, while the soleus is inactive, this would be strong evidence for increased postsynaptic excitability of the alpha-motoneurons. In the event, we found that in untrained subjects, despite the presence of an unexpectedly large H-reflex in midswing, no soleus MEPs were observed at that time. The soleus MEPs were in phase with the soleus electromyographic (EMG) activity during backward walking. Soleus MEPs increased more rapidly as a function of the EMG activity during voluntary activity than during backward walking. Furthermore, a conditioning stimulus to the motor cortex facilitated the soleus H-reflex at rest and during voluntary plantarflexion but not in the midswing phase of backward walking. With daily training at walking backward, the time at which the H-reflex began to increase was progressively delayed until it coincided with the onset of soleus EMG activity, and its amplitude was considerably reduced compared with its value on the first experimental day. By contrast, no changes were observed in the timing or amplitude of soleus MEPs with training. Taken together, these observations make it unlikely that the motor cortex via the CST is involved in control of the H-reflex during the backward step cycle of untrained subjects nor in its progressive adaptation with training. Our observations raise the possibility that the large amplitude of H-reflex in untrained subjects and its adaptation with training are mainly due to control of presynaptic inhibition of Ia-afferents by other descending tracts. collapse abstract

Timing of cortical excitability changes during the reaction time of movements superimposed on tonic motor activity.

Seated subjects were instructed to react to an auditory cue by simultaneously contracting the tibialis anterior (TA) muscle of each ankle isometrically. Focal transcranial magnetic stimulation of the leg area of the motor cortex (MCx) was used to det... expand abstractermine the time course of changes in motor-evoked potential amplitude (MEP) during the reaction time (RT). In one condition the voluntary contraction was superimposed on tonic EMG activity maintained at 10% of maximal voluntary contraction. In the other condition the voluntary contraction was made starting from rest. MEPs in the TA contralateral to the stimulation coil were evoked at various times during the RT in each condition. These were compared to the control MEPs evoked during tonic voluntary activity or with the subject at rest. The RT was measured trial by trial from the EMG activity of the TA ipsilateral to the magnetic stimulus, taking into account the nearly constant time difference between the two sides. The MEPs became far greater than control MEPs during the RT (mean = 332%, SD = 44 %, of control MEPs, P < 0.001) without any measurable change in the background level of EMG activity. The onset of this facilitation occurred on average 12.80 ms (SD = 7.55 ms) before the RT. There was no difference in the onset of facilitation between the two conditions. Because MEPs were facilitated without a change in the background EMG activity, it is concluded that this facilitation is specifically due to an increase of MCx excitability just before voluntary muscle activation. This conclusion is further reinforced by the observation that MEPs evoked by near-threshold anodal stimuli to the MCx were not facilitated during the RT, in contrast to those evoked by near-threshold transcranial magnetic stimulation. However, several observations in the present and previous studies indicate that MEP amplitude may be more sensitive to alpha-motoneuron activity than to motor cortical neuron activity, an idea that has important methodological implications. collapse abstract

The integrated nature of motor cortical function.

Recent studies on the functional organization and operational principles of motor cortical function, taken together, strongly support the notion that the motor cortex controls the muscle activities subserving movements in an integrated manner. For ex... expand abstractample, during pointing the shoulder, elbow and wrist muscles appear to be controlled as a coupled functional system, rather than individually and separately. The pattern of intrinsic connections between motor cortical points is likely part of the explanation of this operational principle. So too is the manner in which muscles and muscle synergies are represented in the motor cortex. However, selection of movement-related muscle synergies is likely a dynamic process involving the functional linking of a variety of motor cortical points, rather than the selection of fixed patterns embedded in the motor cortical circuitry. One of the mechanisms that may be involved in the functional linking of motor cortical points is disinhibition. Thus, motor cortical points are recruited into action by selected excitation as well as by selected release from inhibition. The incoordination of limb movements in patients after a stroke may be understood, at least in part, as a disruption of the connections between motor cortical points and of the neural mechanisms involved in their functional linking. collapse abstract

Expansion of receptive fields in motor cortex by local blockade of GABAA receptors.

Experiments were done in alpha-choralose anesthetized cats to determine whether local disinhibition would expand the sensory receptive field (RF) of motor cortical neurons. Most of the neurons (n = 17) responded only to a rapid high velocity "tap" of... expand abstract the paw or forearm, often requiring movement of a joint, while four cells responded to light touch of the skin. The receptive field of single neurons was re-examined after microiontophoretic ejection of bicuculline (BIC). In all 21 neurons examined, BIC produced an expansion of the RF (mean 4 times before drug). Expansion was seen most often in the proximal-distal axis (17 neurons) but was also commonly seen in the mediolateral axis (9 neurons). The expansion was usually restricted to the dorsal or ventral surface that the original RF was on; in only three neurons in which the pre-drug RF was on the dorsal surface of the paw did the expansion include part or the entire ventral surface. Response thresholds could only be tested in those neurons with touch RFs and showed no evidence of a change within the original RF of these cells. Local disinhibition has previously been shown to allow for the functional linking of motor cortical points, a mechanism that may be involved in the recruitment of movement related muscle synergies. The present results suggest that this may be also accompanied by expansion of the receptive fields. Such a receptive field expansion may be of functional value since motor cortical output neurons would receive sensory input integrated over a larger area of the limb. The role of local inhibitory control of sensory inputs to motor cortex neurons may thus be different than that in sensory cortex where it is thought to restrict receptive field size. collapse abstract

On the soleus H-reflex modulation pattern during walking.

In a recent paper it was claimed that in the majority (9/15) of subjects studied the soleus H-reflex increases progressively during the swing phase of walking. This pattern was at odds with our numerous observations made since 1986, as was the very l... expand abstractarge proportion of subjects reported to exhibit this pattern. We therefore reinvestigated the issue in an extensive series of experiments and detailed subsequent analysis on 21 subjects. In most subjects (13/21) the soleus H-reflex was completely inhibited during most or all of the swing phase (group A). In 8/21 subjects (group B) there was a small H-reflex mean 16% (SD=10.6%) of the value in quiet standing present during most or all of swing, but there was no systematic modulation pattern; the reflex amplitude fluctuated in a seemingly random manner. The difference between the two somewhat arbitrary groups could not be explained on the basis of greater electromyographic activity in the tibialis anterior (TA) during the swing phase or at the time of heel contact. However, by normalizing the mean level of TA activity to the peak level, the ratio was significantly greater for the group A subjects. This highlights the importance of reciprocal inhibition in accounting for the suppression of the soleus H-reflex in swing. In the discussion we emphasize that the presence of a small H-reflex during swing in the group B subjects is unlikely to have any functional role. What is of functional importance is the strong inhibition of the H-reflex during swing which reflects the ensemble of neural mechanisms at play to prevent the unwanted activation of the powerful ankle extensor muscles. collapse abstract

Progressive adaptation of the soleus H-reflex with daily training at walking backward.

When untrained subjects walk backward on a treadmill the amplitude of the soleus H-reflex in midswing is equal to or exceeds the value in stance. This is a surprising result because during the swing phase of backward walking the soleus is inactive an... expand abstractd its antagonist, the tibialis anterior, is active. We suggested that the high amplitude of the soleus H-reflex in late swing reflects task uncertainties, such as estimating the moment of foot contact with the ground and losing balance. In support of this idea we show that when untrained subjects held on to handrails the unexpected high-amplitude H-reflex during midswing was no longer present. We therefore asked whether daily training at this task without grasping the handrails would adaptively modify the H-reflex modulation pattern. In this event, within 10 days of training for 15 min daily, the anticipatory reflex activity at the beginning of training was gradually abated as the subjects reported gaining confidence at the task. However, when adapted subjects were made to walk backward with their eyes shut, the anticipatory reflex activity in midswing returned immediately. The reflex changes as a result of training were not due to changes in the motor activity or kinematics; they are likely part of the motor program controlling backward walking. This adaptive phenomenon may prove to be a useful model for studying the neural mechanisms of motor learning and adaptive plasticity in humans and may be relevant to rehabilitation programs for neurological patients. collapse abstract

Neural mechanisms involved in the functional linking of motor cortical points.

We sought to understand the basic neural processes involved in the functional linking of motor cortical points. We asked which of the two basic neural mechanisms, excitation or inhibition, is required to functionally link motor cortical points. In th... expand abstracte ketamine-anaesthetized cat, a microstimulation electrode was positioned at a point (control point) that was identified by the following three characteristics of the EMG responses: the muscle(s) activated at threshold, any additional muscles recruited by supra-threshold stimulation, and their relative latency. A second distinct point (test point) producing activation of a muscle at a different joint was then identified. At this test cortical point the GABA(A) receptor antagonist bicuculline was ejected iontophoretically, while stimulating the control point near threshold. A combined response was elicited consisting of the response normally elicited at the control point plus that elicited at the test point. Thus, an artificial muscle synergy was produced following disinhibition of the test point. This was never the case when glutamate was ejected at the test point, even when supra-threshold stimuli were used at the control point. Therefore, simply increasing the excitability of a cortical point was not sufficient to release the muscle(s) represented at that point into a muscle synergy. Kynurenate, a broadly acting excitatory amino acid receptor antagonist, ejected at the bicuculline point reversed the effect of bicuculline. This shows that the release phenomenon was mediated synaptically and was not due to spread of the stimulating current. We suggest that release from inhibition may be one of the neural mechanisms involved in functionally linking motor cortical points. This functional linking may be part of the ensemble of motor cortical mechanisms involved in recruitment of muscle synergies. collapse abstract

The special nature of human walking and its neural control.

Walking the way we do is inherently unstable. Sophisticated neurological control systems are required to ensure that we progress and maintain our balance at the same time. Most of what is known about the functional organization of these neurological ... expand abstractcontrol systems is inferred from studies on animals. Here, I compare selected studies on the neural control of human walking with similar studies in reduced animal preparations. The simple monosynaptic reflex appears to be controlled by comparable mechanisms in walking cats and humans. However, peripheral feedback mechanisms suggested to contribute to the switch from stance to swing on the basis of experiments in reduced cat preparations have little influence during human walking. A cat whose spinal cord has been completely transected can be made to walk on a treadmill by drug injections, but such an immediate effect of pharmacological intervention is not seen in humans. However, there have been reports that pharmacological intervention can improve the walking of patients with incomplete spinal cord injury, especially when pharmacological treatment is combined with training. collapse abstract

Integrated motor cortical control of task-related muscles during pointing in humans.

A large body of compelling but indirect evidence suggests that the motor cortex controls the different forelimb segments as a whole rather than individually. The purpose of this study was to obtain physiological evidence in behaving human subjects on... expand abstract the mode of operation of the primary motor cortex during coordinated movements of the forelimb. We approached this problem by studying a pointing movement involving the shoulder, elbow, wrist, and index finger as follows. Focal transcranial magnetic stimulation (TMS) was used to measure the input-output (I/O) curves-a measure of the corticospinal pathway excitability-of proximal (anterior deltoid, AD, and triceps brachii, TB) and distal muscles (extensor carpi radialis, ECR, and first dorsal interosseus, 1DI) during isolated contraction of one of these muscles or during selective co-activation with other muscles involved in pointing. Compared to an isolated contraction of the ECR, the plateau-level of the ECR sigmoid I/O curve increased markedly during co-activation with the AD while pointing. In contrast, the I/O curve of AD was not influenced by activation of the more distal muscles involved in pointing. Moreover, the 1DI I/O curve was not influenced by activation of the more proximal muscles. Three arguments argue for a cortical site of facilitation of ECR motor potentials. First, ECR motor potentials evoked by a near threshold TMS stimulus were facilitated when the AD and ECR were co-activated during pointing but not those in response to a near threshold anodal electrical stimulus. Second, the ECR H reflex was not found to be task dependent, indicating that the recruitment gain of the ECR alpha-motoneuron pool did not differ between tasks. Finally, in comparison with an isolated ECR contraction, intracortical inhibition tested at the ECR cortical site was decreased during pointing. These results suggest that activation of shoulder, elbow, and wrist muscles involved in pointing appear to involve, at least in part, common motor cortical circuits. In contrast, at least in the pointing task, the motor cortical circuits involved in activation of the 1DI appear to act independently. collapse abstract

A re-examination of the possibility of controlling the firing rate gain of neurons by balancing excitatory and inhibitory conductances.

It has been suggested that balancing excitatory and inhibitory conductance levels can control the firing rate gain of single neurons, defined as the slope of the relation between discharge frequency and excitatory conductance. According to this view ... expand abstractthe increase in firing rate produced by an input pathway can be controlled independently of the ongoing firing rate by adjusting the mixture of excitatory and inhibitory conductances produced by other pathways converging onto the neuron. These conclusions were derived from a simple RC-neuron model with no active conductances, or firing threshold mechanism. The analysis of that model considered only the subthreshold behaviour and did not consider the relation between total trans-membrane conductance and firing rate. Similar conclusions were also derived from a simple parallel conductance based model. In this paper I consider, as an example of a repetitively firing neuron, a generic model of cat lumbar alpha-motoneurons with excitatory and inhibitory inputs and a second independent excitatory pathway. The excitatory and inhibitory inputs can be thought of as central descending controls while the second excitatory pathway may represent, for example, the monosynaptic Ia-afferent pathway. I have re-examined the possibility that the firing rate gain of the "afferent" pathway can be controlled independently of the ongoing firing rate by balancing the excitatory and inhibitory conductances activated by the descending inputs. The steady state firing rate of the model motoneuron increased nearly linearly with the excitatory current, as it does in real motoneurons (primary firing range). The model motoneuron also showed a secondary firing range, whose slope was steeper than in primary range. The firing rate gain was measured by increasing the conductance of the "afferent" pathway. The firing rate gain (in the primary and secondary firing range) of the "afferent" pathway was found to be the same regardless of the particular mixture of excitatory and inhibitory conductances acting to produce the ongoing firing rate. This result was obtained for a single-compartment model, as well as for a two-compartment model consisting of an active somatic compartment and a dendritic compartment containing an L-type calcium conductance. Put simply, the firing rate gain of an input to a neuron cannot be controlled by balancing excitatory and inhibitory conductances produced by other independent input pathways, or by the spatial distribution of excitation and inhibition across the neuron. Three potential ways of controlling the firing rate gain are presented in the "Discussion". Firing rate gain can be controlled by actions at the presynaptic terminal, by inhibitory feedback, which is a function of the neuron's firing rate, or by neuromodulator substances that affect intrinsic inward or outward currents. collapse abstract

Quantitative evidence for multiple widespread representations of individual muscles in the cat motor cortex.

We sought to determine why a given muscle appears represented in widespread loci in the motor cortex (MCx). To this end, we microstimulated every 500 microm along medio-lateral rows and recorded the evoked electromyographic (EMG) responses of up to a... expand abstract dozen forelimb muscles of the cat. A consistent finding in all animals studied was that along a given row, distal muscle responses could be elicited from medially situated cortical loci and conversely, proximal muscles responses from laterally situated cortical loci. In many such cases, the evoked EMG responses were such that the largest responses from a distal muscle were obtained by stimulation at a medially situated point and those of a proximal muscle from a laterally situated point. A Spearman correlation analysis showed that there was no correlation between cortical position and where the peak response of a given muscle occurred. These quantitative results strongly support the view that in the forelimb area of the cat MCx there exists widespread 'colonies' of corticospinal neurons with common spinal cord targets. collapse abstract

Force-feedback during human walking.

Control of a 'simple' stretch reflex in humans.

Long-term changes of GABAergic function in the sensorimotor cortex of amputees. A combined magnetic stimulation and 11C-flumazenil PET study.

Primary sensory and motor areas of the cerebral cortex contain organised maps of the body. These maps appear to reorganise after damage to the peripheral parts of the sensory or motor systems, so that the cortical representation of undamaged structur... expand abstractes expands at the expense of the damaged parts. Several studies in animals have suggested that decreased activity of the inhibitory GABAergic neurones is responsible for driving these changes. However, whether similar mechanisms sustain the effects in the longer term in humans is unknown. The present study addressed this question by examining reorganisation of sensorimotor areas of cortex in six unilateral upper limb amputees several years after the initial injury. We measured two independent indices of GABAergic function. Volumes of distribution of GABA(A) receptors were determined from 11C-flumazenil binding measured with positron emission tomography (PET). The strength of inhibition in the motor cortex was measured with paired-pulse transcranial magnetic stimulation. In the six amputees taken as a whole and compared with 24 normal subjects, there was a highly significant increase in 11C-flumazenil binding in the upper limb region of primary sensorimotor cortex bilaterally and in medial frontal cortex of the hemisphere contralateral to the amputation. Surprisingly, however, there was no change in the time course or strength of intra-cortical inhibition in the motor cortex of the amputees compared with matched control subjects. The increased 11C-flumazenil binding may reflect up-regulation of GABA(A) receptors to compensate for a decrease in the GABA content or activity of inhibitory neurones. Up-regulation of GABA(A) receptors may also indicate that long-term changes require stabilisation of cortical organisation. collapse abstract

On the origin of the soleus H-reflex modulation pattern during human walking and its task-dependent differences.

Recently, Brooke and colleagues have suggested "that the strong inhibition arising from passive movement about the knee and hip joints, lays down the base for the soleus H-reflex gain modulation seen during human gait." In particular stretch-evoked a... expand abstractfferent activity from the quadriceps muscle was emphasized as the most important source of movement-induced inhibition of the H-reflex. To test this hypothesis we examined the kinematics and electromyographic (EMG) activity of the leg during human walking and correlated these with the modulation pattern of the soleus H-reflex. To further test the possible contribution of stretch-evoked quadriceps afferent activity to the soleus H-reflex modulation pattern during walking different walking gaits were studied. In one condition subjects were asked to walk with their knee locked in full extension by a rigid knee brace. In a second condition subjects were asked to walk backwards. During normal walking, the soleus H-reflex modulation pattern is strongly correlated with the EMG events of the soleus and tibialis anterior (TA), but not with hip, knee, or ankle angular displacement or velocity. When subjects walked with the knee locked in full extension, the amplitude of the H-reflex, its modulation pattern, and the task-dependent changes of its amplitude were the same as during normal walking. During backward walking, the H-reflex increases in late swing before activity of the soleus has begun and while the knee is flexing, an observation that highlights central control of the H-reflex amplitude. The effects of imposed flexion of the knee in passive subjects were also reexamined. The knee flexion imposed by the experimenter followed the same trajectory as that which occurred during the swing phase of the subject's step cycle. It was found that imposed knee flexions elicited a burst of TA EMG activity with an average latency of 81.6 ms (SD = 21 ms) in six out of eight subjects. Inhibition of the H-reflex, when it occurred, was associated with the occurrence of this burst. When subjects voluntarily flexed their right knee from an initial quiet standing posture, the inhibition of the soleus H-reflex began before flexion of the knee or that of any other leg segment. Once again the onset of inhibition was closely associated with the onset of activity in the TA. In the discussion section the present observations are examined in light of the predictions made by the movement-induced inhibition hypothesis of Brooke et al. It will be concluded that none of the predictions of this hypothesis were corroborated by present tests done during human walking. In consequence, we suggest that the modulation pattern of the H-reflex observed during normal human walking is centrally determined, as are the task-dependent differences of its amplitude (e.g., standing versus the stance phase of human walking). collapse abstract

Studies on the corticospinal control of human walking. I. Responses to focal transcranial magnetic stimulation of the motor cortex.

Experiments were done to determine the extent to which the corticospinal tract is linked with the segmental motor circuits controlling ankle flexors and extensors during human walking compared with voluntary motor tasks requiring attention to the lev... expand abstractel of motor activity. The motor cortex was activated transcranially using a focal magnetic stimulation coil. For each subject, the entire input-output (I-O) curve [i.e., the integral of the motor evoked-potential (MEP) versus stimulus strength] was measured during a prescribed tonic voluntary contraction of either the tibialis anterior (TA) or the soleus. Similarly, I-O curves were measured in the early part of the swing phase, or in the early part of the stance phase of walking. The I-O data points were fitted by the Boltzmann sigmoidal function, which accounted for >/=80% of total data variance. There was no statistically significant difference between the I-O curves of the TA measured during voluntary ankle dorsiflexion or during the swing phase of walking, at matched levels of background electromyographic (EMG) activity. Additionally, there was no significant difference in the relation between the coefficient of variation and the amplitude of the MEPs measured in each task, respectively. In comparison, during the stance phase of walking the soleus MEPs were reduced on average by 26% compared with their size during voluntary ankle plantarflexion. Furthermore, during stance the MEPs in the inactive TA were enhanced relative to their size during voluntary ankle plantarflexion and in four of six subjects the TA MEPs were larger than those of the soleus. Finally, stimulation of the motor cortex at various phases of the step cycle did not reset the cycle. The time of the next step occurred at the expected moment, as determined from the phase-resetting curve. One interpretation of this result is that the motor cortex may not be part of the central neural system involved in timing the motor bursts during the step cycle. We suggest that during walking the corticospinal tract is more closely linked with the segmental motor circuits controlling the flexor, TA, than it is with those controlling the extensor, soleus. However, during voluntary tasks requiring attention to the level of motor activity, it is equally linked with the segmental motor circuits of ankle flexors or extensors. collapse abstract

Intracortical connections between motor cortical zones controlling antagonistic muscles in the cat: a combined anatomical and physiological study.

Experiments were done on nine cats anaesthetized with pentobarbitone to determine whether motor cortical zones controlling antagonistic muscles are synaptically interconnected. Motor cortical zones controlling wrist flexors, or extensors, were identi... expand abstractfied by microstimulation and intramuscular electromyographic recordings (microstimulation: 11 pulses at 333 pulses/s, current 10-40 microA). The position of each zone of interest was marked by a small ink spot on the surface of the cortex and on a scaled drawing of the cortical surface (cruciate region). Following the identification of wrist flexor and extensor zones the anterograde tracer biocytin was injected into one, or two, wrist extensor zones at three depths (400, 800 and 1500 microm) from the cortical surface. A small injection of horseradish peroxidase (HRP)--producing a dark brown spot of approximately 300-500 microm--was made in layer II-III of one or more wrist flexor zones. Similar HRP injections were made in the deep layers of wrist extensor zones that were not labelled by biocytin. The HRP injections served to mark the position of potential targets of biocytin-labelled fibres. In some experiments the biocytin was injected into a wrist flexor zone and HRP was deposited in one or more wrist extensor zones. Biocytin-labelled fibres (blue) were found throughout the expanse of the forelimb representation zone, as has been previously reported. More specifically, in all animals biocytin-labelled fibres were found in identified cortical zones controlling the same muscle(s) as well as in zones controlling an antagonist(s). Club-like swellings, indicative of synaptic boutons, were observed on these fibres. The density of labelled fibres was greater in the upper cortical layers (II-III), but a large number of terminals were also present in the lower cortical layers (V-VI). We conclude that there exist intracortical circuits linking motor cortical zones controlling antagonistic muscles. Elucidating the nature and function of these circuits is likely to be important for understanding the mode of operation of the motor cortex. collapse abstract

Differential control of reciprocal inhibition during walking versus postural and voluntary motor tasks in humans.

Experiments were done to determine whether the strength of reciprocal inhibition from ankle flexors to extensors can be controlled independently of the level of ongoing motor activity in a task-dependent manner. In this paper we use the term reciproc... expand abstractal inhibition in the functional sense--inhibition of the antagonist(s) during activity of the agonist(s)--without reference to specific neural pathways that may be involved. The strength of reciprocal inhibition of the soleus alpha-motoneurons was determined by measuring the amplitude of the H reflex during voluntary, postural, and locomotor tasks requiring activity of the ankle flexor tibialis anterior (TA). Differences in the strength of reciprocal inhibition between tasks were determined from plots of the soleus H reflex amplitude versus the mean value of the TA electromyogram (EMG). Additionally, in tasks involving movement, the correlation between the H reflex amplitude and the joint kinematics was calculated. In most subjects (15 of 22) the soleus H reflex decreased approximately linearly with increasing tonic voluntary contractions of the TA. The H reflex also decreased approximately linearly with the TA EMG activity when subjects where asked to lean backward. There were no statistical differences between the regression lines obtained in these tasks. In some subjects (7 of 22), however, the H reflex amplitude was independent of the level of TA EMG activity, except for a sudden drop at high levels of TA activity (approximately 60-80% of maximum voluntary contraction). The type of relation between the soleus H reflex and the TA EMG activity in these tasks was not correlated with the maximum H reflex to maximum M wave (Hmax/Mmax) ratio measured during quiet standing. In marked contrast, during the swing phase of walking--over the same range of TA EMG activity as during the tonic voluntary contraction task--the H reflex was reduced to zero in most subjects (24 of 31). In seven subjects the H reflex during the swing phase was reduced to some 5% of the value during quiet standing. The same result was found when subjects were asked to produce a stepping movement with one leg (OLS) in response to an auditory "go" signal. Additionally, in the OLS task it was possible to examine the behavior of the H reflex during the reaction time and thus to evaluate the relative contribution of central commands versus movement-related afferent activity to the inhibition of the soleus H reflex. In 11 of 12 subjects the H reflex attained its minimum value before either the onset of EMG activity or movement of any of the leg joints. It is significant that the H reflex was most powerfully inhibited during the swing phase of walking and the closely related OLS task. The H reflex was also measured during isolated ankle dorsiflexion movements. The subjects were asked to track a target displayed on a computer screen with dorsiflexion movements of the ankle. The trajectory of the target was the same as that of the ankle during the swing phase of walking. The soleus H reflexes were intermediate in size between the values obtained in the tonic contraction task and the walking or OLS tasks. A negative, but weak, correlation (r2 < 0.68) between the soleus H reflex and the TA EMG was found in 3 of 10 subjects. Furthermore, there was no correlation between the H reflex amplitude and the ankle angular displacement or angular velocity. In this task, as in the OLS task, the H reflex began to decrease during the reaction time before the onset of TA EMG activity. We conclude that the strength of reciprocal inhibition of the soleus alpha-motoneuron pool can thus be controlled independently of the level of motor activity in the ankle flexors. The strength of the inhibition of the antagonist(s) depends on the task, and for each task the strength of the inhibition is not necessarily proportional to the level of motor activity in the agonist(s). (ABSTRACT TRUNCATED) collapse abstract

Neurophysiological methods for studies of the motor system in freely moving human subjects.

In this paper, the following experimental methods for studies of the motor system in freely moving human subjects will be considered: (i) eliciting the H-reflex and understanding its use as a test response, (ii) methods to measure reciprocal inhibiti... expand abstracton between antagonist muscles, (iii) methods to measure presynaptic inhibition of Ia-afferent terminals in the spinal cord, (iv) certain aspects of the interpretation of peri-stimulus time histograms (PSTH) of single motor unit discharge, and finally, (v) stimulation of the motor cortex and the measurement of response parameters that may reflect task dependent changes. Two closely related ideas bearing directly on these methods will be emphasized--the influence of the background level of motor activity on input output properties of the neural pathway investigated and the operating point on the input-output curves at which the experimental variable is measured. Finally, in the discussion a simple model that is easily understandable in geometric terms is presented to help predict and interpret the outcome of these sorts of experiments. collapse abstract

Input-output properties and gain changes in the human corticospinal pathway.

Experiments were done to determine the form of the input-output relation (i.e. stimulus intensity vs response amplitude) of the corticospinal pathway of the first dorsal interosseous and the tibialis anterior, respectively. Our purpose was to determi... expand abstractne from these quantitative relations which input-output parameters would be useful measures in studies dealing with motor cortical task dependence. The motor cortex was excited by focal transcranial magnetic stimuli and the evoked motor response were recorded with surface electromyographic electrodes. In some experiments the discharge probability of single motor units in response to magnetic stimuli of increasing intensity was determined from intramuscular recordings. For both muscles the form of the input-output relation was sigmoidal. The steepness of the relation increased, up to 4-7 times the value at rest, with increasing tonic background activity. The threshold decreased, but only slightly, with increasing tonic background activity. The minimum value of the threshold was reached at activation levels of about 10-20% of the maximum tonic effort, whereas the steepness of the relation reached its maximum at higher activation levels, typically about 30-40% of the maximum tonic effort. These observations imply that these two input-output parameters of the corticospinal pathway - one reflecting the bias level (threshold) and the other the gain (slope) - are determined by different neural mechanisms. The plateau level of the sigmoidal input-output relation was not influenced by the background activation level, except that in some subjects (4/9) it could not be reached when no background motor activity was present. This was probably due, for the most part, to limitation of the maximum stimulator output. Additionally, this finding may reflect a change in the intrinsic excitability of the motor cortex in going from rest to activity, or that convergent inputs from different descending and afferent systems are required for maximal activation of motoneuron pools. Thus, the threshold, steepness and plateau level characterize the input-output parameters of the human corticospinal pathway for a given level of motor activity. In contrast to the nonlinear input-output relation of the corticospinal pathway as whole, which includes the motoneuron pool and any spinal interneuronal relays, the discharge probability of all single motor units was a linearly increasing function of the stimulus strength (r> or =0.9, P<0.01). Thus, the sigmoidal input-output relation of the corticospinal pathway, as a whole, is not due to the input-output properties of single motoneurons. The possible neural mechanisms which underlie the shape and parameters of the input-output relation as well as the methodological implications of the results are considered. collapse abstract

The effects of baclofen on the stretch reflex parameters of the cat.

Experiments were done in cats decerebrated at the precollicular postmammillary level to determine how a tonic increase of presynaptic inhibition of the intraspinal terminals of muscle spindle afferents changes the mechanical properties of the soleus ... expand abstractstretch reflex (s.r.). Baclofen, a specific GABAB receptor agonist, was injected i.v. (1-2 mg/kg) so as to induce a tonic increase in presynaptic inhibition. The effects of baclofen on the stiffness and threshold of the s.r. were determined, respectively, from plots of stiffness vs background force and force vs length (length-tension plot). Baclofen, at these doses, had no effect on the excitation-contraction coupling properties of muscle or on the intrinsic stiffness-force relation. Changes of the soleus background force, required to obtain the stiffness vs force plots, were produced by stimulation of the contralateral common peroneal nerve or the posterior tibial nerve and occasionally by electrical stimulation in the area of the red nucleus. The stiffness of the s.r. as a function of the background force level was determined by stretching the muscle with a square pulse of 1-2 mm amplitude and 200-300 ms duration. The stiffness at each force level was calculated by dividing the change in force by the change in length, at a point where the force trace had stabilized. The length-tension relation of the s.r. was determined by stretching the muscle 12-17 mm at a constant rate of 1-2 mm/s. At all force levels, baclofen produced a significant decrease (40% or more) in the s.r. stiffness, within 10-15 min of injection as determined from the stiffness-force plots. The length-tension plus revealed that the decrease of s.r. stiffness was always accompanied by an increase in the s.r. threshold (typically 2-3 mm). It is suggested, therefore, that the s.r. threshold is not an independent variable, depending on the membrane potential of the alpha-motoneurons, and additionally on the level of presynaptic inhibition of the muscle spindle afferent terminals. The present results also imply that it may be possible for the CNS to adaptively modify the s.r. stiffness via presynaptic inhibition of the intraspinal terminals of muscle afferents. However, any such change of s.r. stiffness will be accompanied by a change in the s.r. threshold. collapse abstract