Charles Capaday

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

Abstractu2002Experiments 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 determine 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≥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.

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 inhibition 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.

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 control 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.

Cortical control of human soleus muscle during volitional and postural activities studied using focal magnetic stimulation

The surface-recorded electromyographic (EMG) responses evoked in the ankle musculature by focal, transcranial, magnetic stimulation of the motor cortex were studied in healthy human subjects. Such soleus evoked motor responses (EMRs) were characterised over a wide range of background levels of motor activity and using different stimulus intensities. EMRs were recorded during predominantly (1) volitional and (2) postural tasks. In the former task subjects were seated and voluntarily produced prescribed levels of soleus activation by reference to a visual monitor of EMG. In the latter task subjects assumed standing postures without EMG feedback. Comparison of the EMRs of soleus, traditionally considered a slow anti-gravity extensor muscle, during these tasks was used to evaluate its cortical control in primarily volitional versus primarily postural activities. The form of soleus EMRs produced by single magnetic cortical stimuli comprised an initial (approx. 30 ms) increase and subsequent (approx. 50 ms) depression of EMG. Cortical stimulation could elicit substantial excitatory soleus EMG responses; for example, responses evoked by mild, magnetic stimuli (125% threshold for inducing a response in the relaxed muscle) as subjects exerted full voluntary plantarflexor effort averaged almost 20% of the maximum M-wave which could be elicited by an electrical stimulus to the posterior tibial nerve. Excitatory EMRs could be elicited in the voluntarily relaxed soleus muscle of the majority of subjects during sitting. The amplitude of soleus responses, induced by threshold stimuli for the relaxed state or approximately 125% threshold intensity, increased approximately linearly with background EMG over a wide range of volitional contraction levels. By contrast, there was no systematic change in the latency of excitatory soleus EMRs with increasing voluntary effort. The excitatory responses evoked in the voluntarily relaxed soleus of seated subjects by magnetic stimulation were regularly facilitated by incremental, voluntary contraction of the contralateral ankle extensors in a graded manner. However, such facilitation of responses was not observed when subjects voluntarily activated the muscle in which EMRs were elicited. The pattern of the responses elicited in soleus by magnetic stimulation during the postural task generally resembled that found during the volitional task. The amplitudes of excitatory soleus EMRs at a given stimulus intensity, obtained when subjects stood quietly, leaned forwards or stood on their toes to produce differing levels of ankle extensor contraction, increased with background EMG. Overall, the relationship between the size of cortically evoked soleus responses and the tonic level of motor activity, observed in individual subjects at matched stimulus intensities, did not consistently differ between postural and volitional tasks. The present results suggest that the motor cortex is potentially capable of exerting rapid regulation of the soleus muscle, and presumably other ankle extensors, not only when the muscle participates in volitional tasks but also when it is engaged in postural maintenance.

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 the ketamineanaesthetized 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 GABAA 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.

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 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 1u2003cm along a grid drawn on a tight‐fitting polyester cap placed on the subjects 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 muscles mean MEP was measured at each stimulation site. The area of a muscles representation was measured by a pixel‐counting algorithm. The optimal point of each muscles 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.

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 example, 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.

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

Abstractu2002Experiments 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 identified by microstimulation and intramuscular electromyographic recordings (microstimulation: 11 pulses at 333 pulses/s, current 10–40 μA). 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 μm) from the cortical surface. A small injection of horseradish peroxidase (HRP) – producing a dark brown spot of approximately 300–500 μm – 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.

Intensity modulation of TMS-induced cortical excitation: Primary motor cortex

The intensity dependence of the local and remote effects of transcranial magnetic stimulation (TMS) on human motor cortex was characterized using positron‐emission tomography (PET) measurements of regional blood flow (BF) and concurrent electromyographic (EMG) measurements of the motor‐evoked potential (MEP). Twelve normal volunteers were studied by applying 3 Hz TMS to the hand region of primary motor cortex (M1hand). Three stimulation intensities were used: 75%, 100%, and 125% of the motor threshold (MT). MEP amplitude increased nonlinearly with increasing stimulus intensity. The rate of rise in MEP amplitude was greater above MT than below. The hemodynamic response in M1hand was an increase in BF. Hemodynamic variables quantified for M1hand included value‐normalized counts (VNC), intensity (z‐score), and extent (mm3). All three hemodynamic response variables increased nonlinearly with stimulus intensity, closely mirroring the MEP intensity‐response function. VNC was the hemodynamic response variable which showed the most significant effect of TMS intensity. VNC correlated strongly with MEP amplitude, both within and between subjects. Remote regions showed varying patterns of intensity response, which we interpret as reflecting varying levels of neuronal excitability and/or functional coupling in the conditions studied. Hum Brain Mapp, 2005.

A re-examination of the effects of instruction on the long-latency stretch reflex response of the flexor pollicis longus muscle

We re-examined the issue of how a subjects intention to react to a joint perturbation may modulate the long-latency M2 stretch reflex response. The experiments were done on the flexor pollicis longus muscle (FPL) of the human thumb, for which there is evidence that its M2 reflex response is mediated, at least in part, by a pathway that traverses the motor cortex. The participation of the cerebral cortex in the genesis of the M2 reflex response may allow for a modulation of its amplitude, based on the intention of the subject. To test whether the M2 response is genuinely modulated by the subjects intention, we examined the magnitude of this response as a function of the FPL background level of activation, measured by the surface rectified and filtered EMG. The subject was instructed either to oppose the perturbation as quickly as possible, not to react, or to relax as quickly as possible after the onset of the perturbation. The time integral of the long latency FPL EMG response, computed between 40 and 70 ms following the onset of stretch, was plotted against the mean torque produced by the distal inter-phalangeal joint of the thumb, or against the mean background FPL EMG. There were no significant differences in the FPL M2 EMG responses for different instructions. The amplitude of the reflex response was dependent only — in an approximately linear manner — on the background level of muscle activation. The total joint stiffness (intrinsic plus reflex) was also calculated for each combination of instruction and background torque. This variable was calculated over a time interval (from 75 to 105 ms) that included the torque due to the M2 reflex response superimposed on the background torque, but was well before any voluntary reaction. Again, there were no significant differences in joint stiffness as a result of the instruction. We therefore conclude that, despite a cortical contribution to the M2 stretch reflex response, this response is not influenced by the intention of the subject on how to react to a perturbation.