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Modulation of a Hoffmann (H)-reflex following transcranial magnetic stimulation (TMS) has been used to assess the nature of signals transmitted from cortical centers to lower motor neurons. Further characterizing the recruitment and time-course of the TMS-induced effect onto the soleus H-reflex adds to the discussion of these pathways and may improve its utility in clinical studies. In 10 healthy controls, TMS was used to condition the soleus H-reflex using TMS intensities from 65 to 110% of the resting motor threshold (RMT). Early facilitation [− 5 to − 3 ms condition-test (C-T) interval] was evident when TMS was 110% of RMT (P

Transcutaneous spinal stimulation is a noninvasive method that can activate dorsal and/or ventral roots depending on the location and intensity of stimulation. Reflex root-evoked potentials (REPs) were studied in muscles that traditionally evoke large (soleus) and small H-reflexes (tibialis anterior), as well as muscles where H-reflexes are difficult to study (hamstrings). This study characterizes the interaction of the REP and the motor-evoked potential (MEP). Transcranial magnetic stimulation (TMS) delivered 11–25 ms before spinal stimulation resulted in more than linear summation of the two responses. Because of overlap, the modulation was quantified after subtracting the contribution of the conditioning MEP or REP. At rest, the mean-rectified soleus response was facilitated by up to ~250 μV (21-times the MEP or 161 % of the REP). The increases were more reliable during a voluntary contraction (up to ~300 μV, 517 % of the MEP or 181 % of the REP). At the 13-ms interval, the mean-rectified response in the pre-contracted hamstrings was increased by 227 % of the MEP or 300 % of the REP. In some subjects, TMS could also eliminate the post-activation depression produced using two spinal stimuli, confirming that the interaction can extend to presynaptic spinal neurons. The spatiotemporal facilitation in tibialis anterior was not significant. However, the large MEP was facilitated when the spinal stimulus preceded TMS by 100–150 ms, presumably because of rebound excitation. These strong interactions may be important for inducing motor plasticity and improved training procedures for recovery after neurological damage.

The human soleus H-reflex is commonly tested as an indicator of the reflex excitability of the calf muscles with infrequent stimuli to a subject seated and at rest. However, the reflex varies widely with the level of voluntary contraction and with the time history of stimulation. We studied two aspects of this variation. Antagonist (tibialis anterior) activation decreases the response, while increasing agonist (soleus) activation increases the H-reflex to a peak after which it declines. In subjects with large H-reflexes at rest, the reflex peaked at low levels of contraction. In contrast, in subjects with small H-reflexes at rest, the reflex peaked at higher levels of contraction for reasons that were elucidated using a realistic computer model. A parabolic curve fitted the maximum amplitude of the H-reflex in the model and over the entire range of contractile levels studied. The second aspect studied was post-activation depression or homosynaptic depression (HD), which has been described previously as a reduction of a second H-reflex elicited shortly after an initial reflex. We confirmed the presence of HD in resting, seated subjects for intervals up to 4 s. However, by voluntarily activating the soleus muscle, HD was drastically reduced when seated and abolished when standing. This suggests that HD may be absent in normal, functional movements and perhaps in clinical conditions that alter H-reflexes. Meaningful, quantitative measurements of reflex excitability can only be made under voluntary activity that mimics the condition of interest.

The purpose of this study was to investigate short-term effects of walking with functional electrical stimulation (FES) on inhibitory and excitatory spinal reflexes in healthy subjects. The FES was applied to the common peroneal (CP) nerve during the swing phase of the step cycle when the ankle flexors are active. We have previously shown that corticospinal excitability for the tibialis anterior (TA) muscle increased after 30 min of FES-assisted walking. An increase of corticospinal excitability could be due to the changes in spinal and/or cortical excitability. Thus, we wished to examine whether a short-term application of FES would increase spinal motoneuronal excitability. Changes could also result from effects on inhibitory as well as excitatory pathways, but to our knowledge no studies have investigated short-term effects of FES on spinal inhibitory pathways. Therefore, we measured reciprocal and presynaptic inhibition, as well as reflex excitability, before and after FES-assisted walking. As controls, effects of FES-like stimulation at rest and walking without stimulation were tested in separate sessions. The TA H-reflex amplitude did not increase after FES in any of the conditions tested, so we have no evidence that FES increases spinal excitability for the TA. The soleus H-reflex decreased slightly (10%) after FES-assisted walking, and remained decreased for at least 30 min. However, the control experiment indicated that this decrease was associated with walking and not with stimulation. Thirty minutes of FES did not produce any significant effects on spinal inhibitory pathways examined in the present study. In conclusion, the soleus H-reflex showed a small but consistent decrease and no spinal circuits examined showed an increase, as was observed in the corticospinal excitability. Thus, we suggest that a short-term application of FES increases the excitability of the cortex or its connections to the spinal cord more effectively than that of spinal pathways.

Some neurotransmitters act consistently on the central pattern generator (CPG) for locomotion in a wide range of vertebrates. In contrast, acetylcholine (ACh) and noradrenaline (NA) have various effects on locomotion in different preparations. The roles of ACh and NA have not been studied in amphibian walking, so we examined their effects in an isolated spinal cord preparation of the mudpuppy ( Necturus maculatus). This preparation contains a CPG that produces locomotor activity when N-methyl- D-aspartic acid (NMDA), an excitatory amino acid agonist, is added to the bath. The addition of carbachol, a long acting ACh agonist, to the bath disrupted the walking rhythm induced by NMDA, while not changing the level of activity in flexor and extensor motoneurons. Adding clonidine, an alpha(2)-noradrenergic agonist, had no effect on the NMDA-induced walking rhythm. Physostigmine, an ACh-esterase inhibitor, disrupted the walking rhythm, presumably by potentiating the effects of endogenously released ACh. Atropine, an ACh antagonist that binds to muscarinic ACh receptors, blocked the effects of carbachol, indicating that the action is mediated, at least in part, by muscarinic receptors. In the absence of carbachol, atropine had no effect. Locomotion was not induced by carbachol, atropine or clonidine in a resting spinal cord preparation. Cholinergic actions do not seem to be essential to the CPG for walking in the mudpuppy, but ACh may convert a rhythmic walking state to a more tonic state with occasional bursts of EMG activity for postural adjustments.

Cutaneous reflexes in lower limb muscles were recorded from healthy human subjects after non-noxious electrical stimulation of superficial peroneal (SP), sural and distal tibial nerves while subjects: (1) made graded voluntary contractions of the ankle and knee extensor and flexor muscles while mimicking late stance or heel strike limb positions; and (2) walked on a treadmill at speeds of 2 and 4 km/h. During standing, net reflexes were predominantly suppressive and graded with background EMG. In contrast, during walking net reflexes were mostly facilitatory and uncorrelated with background EMG. Opposite signs (negative during standing, positive during walking) and significant differences of the reflex ratio (net reflex/background EMG) were seen in most leg muscles. The nerve stimulated did not determine the sign of the net reflex while standing: nerve specificity was absent. We suggest that during standing, where maintenance of posture is of primary importance, there is a reduction of effort that led to increased cutaneous input (i.e., a global suppressive response), while during walking there is a modulation of reflexes which is independent of muscle activation level but closely tied to events occurring in the step cycle.

The aims of the present study were to: (1) study the role of serotonin (5-HT) in modulating the central pattern generator (CPG) underlying locomotion in the mudpuppy (Necturus maculatus); (2) investigate whether there is an intrinsic spinal serotonergic system. These aims were achieved by the use of pharmacological and immunocytochemical methods. To study modulation of the locomotor pattern and rhythm, we applied 5-HT, its uptake blocker zimelidine, and a variety of 5-HT receptor agonists and antagonists to an in vitro brainstem-spinal cord preparation isolated from the mudpuppy. The preparation consisted of the first five segments of the spinal cord and the right forelimb attached by the brachial plexus. The spinal CPG for locomotion was activated chemically by adding NMDA to the superfusing solution. During locomotion, bipolar electromyographic (EMG) recordings were made unilaterally from flexor and extensor ulnae muscles. 5-HT on its own did not induce locomotion, but it did have a profound modulatory effect on NMDA-induced locomotion. 5-HT produced a dose-dependent increase in the overall cycle duration and enhanced the EMG burst duration. Use of zimelidine indicated that there is an endogenous release of 5-HT which modulated the locomotor rhythm. The endogenous release was antagonized by 5-HT1/5-HT2 receptor antagonist methiothepin. Immunocytochemical analysis, in which the entire spinal cord of the mudpuppy was used, revealed that there were more than one type of spinal serotonergic neuron. They were differentiated according to the cell diameter, shape, and arborization pattern of their processes. These neurons were located within the central gray matter ventrolateral to the central canal. Our results suggest that 5-HT plays an important role in modulating the locomotor CPG in the mudpuppy, by acting through a well-developed spinal serotonergic system. This is in contrast to what has been reported in higher vertebrates, where serotonergic innervation is derived from supraspinal structures.

This paper contrasts responses in the soleus muscle of normal human subjects to two major inputs: the tibial nerve (TN) and the corticospinal tract. Paired transcranial magnetic stimulation (TMS) of the motor cortex at intervals of 10-25 ms strongly facilitated the motor evoked potential (MEP) produced by the second stimulus. In contrast, paired TN stimulation produced a depression of the reflex response to the second stimulus. Direct activation of the pyramidal tract did not facilitate a second response, suggesting that the MEP facilitation observed using paired TMS occurred in the cortex. A TN stimulus also depressed a subsequent MEP. Since the TN stimulus depressed both inputs, the mechanism is probably post-synaptic, such as afterhyperpolarization of motor neurons. Presynaptic mechanisms, such as homosynaptic depression, would only affect the pathway used as a conditioning stimulus. When TN and TMS pulses were paired, the largest facilitation occurred when TMS preceded TN by about 5 ms, which is optimal for summation of the two pathways at the level of the spinal motor neurons. A later, smaller facilitation occurred when a single TN stimulus preceded TMS by 50-60 ms, an interval that allows enough time for the sensory afferent input to reach the sensory cortex and be relayed to the motor cortex. Other work indicates that repetitively pairing nerve stimuli and TMS at these intervals, known as paired associative stimulation, produces long-term increases in the MEP and may be useful in strengthening residual pathways after damage to the central nervous system.

Stimulating sensory afferents can increase corticospinal excitability. Intensive use of a particular part of the body can also induce reorganization of neural circuits (use-dependent plasticity) in the central nervous system (CNS). What happens in the CNS when the nerve stimulation is applied in concert with the use of particular muscle groups? The purpose of this study was to investigate short-term effects of electrical stimulation of the common peroneal (CP) nerve during walking on motor-evoked potentials (MEPs) in the ankle flexors and extensors in healthy subjects. Since the stimulation was applied during the swing phase of the step cycle when the ankle flexors are active, this is referred to as functional electrical stimulation (FES). The following questions were addressed: (1) can FES during walking increase corticospinal excitability more effectively than passively received repetitive nerve stimulation and (2) does walking itself improve the descending connection. FES was delivered using a foot drop stimulator that activates ankle dorsiflexors during the swing phase of the step cycle. MEPs in the tibialis anterior (TA) and soleus muscles were measured before, between, and after periods of walking with or without FES, using transcranial magnetic stimulation. After 30 min of walking with FES, the half-maximum peak-to-peak MEP (MEP(h)) in the TA increased in amplitude and this facilitatory effect lasted for at least 30 min. In contrast, walking had no effects on the TA MEP(h) without FES. The increase in the TA MEP(h) with FES (approximately 40%) was similar to that with repetitive CP nerve stimulation at rest. The soleus MEP(h) was also increased after walking with FES, but not without FES, which differs from the previous observation with CP nerve stimulation at rest. With FES, the TA silent period at MEP(h) was unchanged or slightly decreased, while it increased after walking without FES. Increased cortical excitability accompanied by unchanged cortical inhibition (no changes in the silent period with FES) suggests that FES did not simply increase general excitability of the cortex, but had specific effects on particular cortical neurons.

Motor-evoked potentials (MEP) in the tibialis anterior (TA) muscle were shown to be facilitated by repetitive electrical stimulation of the common peroneal (CP) nerve at intensities above motor threshold. The TA electromyogram (EMG) and ankle flexion force were recorded in response to transcranial magnetic stimulation (TMS) of the leg area of the motor cortex to evaluate the excitability of cortico-spinal-muscular pathways. Repetitive stimulation of the CP nerve at 25 Hz for 30 min increased the MEP by 50.3 +/- 13.6% (mean +/- S.E.) at a TMS intensity that initially gave a half-maximum MEP (MEPh). In contrast the maximum MEP (MEPmax) did not change. Ankle flexion force (103 +/- 21.9%) and silent period duration (75.3 +/- 12.9%) also increased. These results suggest an increase in corticospinal excitability, rather than total connectivity due to repetitive CP stimulation. Facilitation was evident after as little as 10 min of stimulation and persisted without significant decrement for at least 30 min after stimulation. The long duration of silent period following CP stimulation (99.2 +/- 14.8 ms) suggests that this form of stimulation may have effects on the motor cortex. To exclude the possibility that MEPh facilitation was primarily due to sensory fibre activation, we performed several control experiments. Preferentially activating Ia muscle afferents by vibration in the absence of motor activity had no significant effect. Cutaneous afferent activation via stimulation of the superficial peroneal nerve increased the amplitude of responses at MEPmax rather than MEPh. Concurrent tendon vibration and superficial peroneal nerve stimulation failed to facilitate TA MEP responses. In summary, repetitive electrical stimulation of the CP nerve elicits lasting changes in corticospinal excitability, possibly as a result of co-activating motor and sensory fibres.

Effects of inhibitory neurotransmitters on the locomotor rhythm and pattern generation were investigated using an in vitro preparation isolated from the mudpuppy (Necturus maculatus). The preparation consisted of the first five segments of the spinal cord and the right forelimb attached by the brachial nerves. During N-methyl-d-aspartate (NMDA)-induced locomotion, the rhythmic motor output (EMG) was recorded unilaterally from elbow flexor and extensor muscles. While neither glycine nor gamma-aminobutyric acid (GABA)-related substances induced locomotion in the absence of NMDA, they modulated NMDA-induced locomotion. Bath application of glycine and GABA suppressed the rhythmic motor pattern induced by NMDA. Addition of glycine receptor antagonist strychnine or GABA(A) receptor antagonist bicuculline disrupted the phase relationship between antagonistic motor pools during ongoing locomotion, thereby changing the normal alternating pattern into synchronous EMG bursts. Both the GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen mimicked the effects of GABA as they either slowed down or stopped locomotion. Nipecotic acid, a GABA uptake blocker, had a similar effect. This suggested that an endogenous release of GABA modulated the locomotor rhythm. The endogenous release was antagonized by the GABA(A) and GABA(B) receptor antagonists bicuculline and CGP-35348, respectively. Immunocytochemistry revealed that glycine and GABA-positive neurons and fibers were present in mudpuppy spinal cord. Although the GABAergic neurons were more numerous than glycinergic neurons, both cell types contributed processes directed towards the white matter and occasionally towards the ependymal lining of the central canal. Our results suggest that inhibitory neurotransmitters exert powerful actions upon the neuronal network governing forelimb locomotion in the mudpuppy. The effects we observed may be mediated by a network of segmentally distributed glycinergic and GABAergic spinal neurons.

Since its initial description in 1883, the Jendrássik maneuver (JM) has been used in clinical neurological practice as an effective means of potentiating the tendon tap in neurologically impaired patients. The JM also potentiates its electrical analogue, the Hoffman (H-) reflex, but the mechanism of the reflex modulation has not been clearly established. We studied soleus H-reflex modulation in neurologically intact subjects while at rest and during a mild plantarflexion contraction (EMG level equivalent to approximately 10% maximum voluntary contraction). The control H-reflex was elicited by stimulating the tibial nerve in the popliteal fossa with single pulses of 1 ms duration. Conditioning of the reflex was by: (1) increasing segmental presynaptic inhibition via common peroneal nerve (CP) stimulation; (2) pulling the arms and clenching the teeth (JM); or (3) applying both together (JM+CP). CP stimulation significantly (P0.05) suppressed the H-reflex (50% Hmax), while JM significantly (P0.05) facilitated it during contraction. From either an analysis of the grouped data or by a within-subject analysis, we found that the combined effect of stimulating JM+CP was significantly lower than JM alone, but did not differ from control values or from CP alone. The simplest mechanism would be that the effects of the two sum algebraically on the interneurones producing segmental presynaptic inhibition of the H-reflex.

Locomotion was compared in an intact and in-vitro preparation of the adult mudpuppy (Necturus maculatus). The intact animals walked on an aquatic treadmill while in-vitro preparations were made to walk with a bath application of the excitatory amino acid NMA (N-methyl DL-aspartate). EMG recordings of shoulder muscles (pectoralis, latissimus dorsi, dorsalis scapulae, and procoracohumeralis) and elbow muscles (brachialis and extensor ulnae) were obtained from intact animals while recordings were made from only the elbow muscles in-vitro. The in-vitro preparation required magnesium in the bath to initiate and maintain locomotion, consistent with an NMDA mediated response. Also consistent with an NMDA response was the finding that glycine potentiated the NMA induced locomotion in-vitro. The range of cycle durations seen in-vitro was well within the range seen in the intact animal, while gait analysis demonstrated the similarity of intact and in-vitro locomotor cycles. In spite of these very similar locomotor patterns there are interesting differences in the patterned output seen in-vitro, such as the absence of a second burst in the brachialis muscle in-vitro.

Small, rapid stretches were applied to the soleus muscle during the stance phase of walking by lifting the forefoot with a pneumatic device. Stretch responses were induced in the soleus muscle by the disturbance. The amplitude and time course of the responses from the soleus muscle were a function of both the kinematics of the disturbance and the time in the step cycle when the disturbance was applied. The step cycle was divided into 16 equal time parts, and data obtained within each of these parts were averaged together. The electromyographic (EMG) response of the soleus muscle showed a time course that was similar to the time course of the angular velocity induced by the disturbance at the ankle. Three linear equations were used to predict the EMG response from the soleus muscle as a function of the angular kinematics of the disturbance: 1) velocity, 2) velocity and displacement, 3) velocity, displacement and acceleration. Introduction of a pure delay between the EMG and the kinematics substantially improved the predictions. Most of the variance (70%) in the EMG response could be accounted for by the velocity of the disturbance alone with an optimal delay (average 38 ms). Inclusion of a displacement term significantly increased the variance accounted for (85%), but further addition of an acceleration term did not. Since the velocity of the disturbance accounted for most of the variance, the reflex gain was estimated from the velocity coefficient. This coefficient increased in a ramp-like fashion through the early part of the stance phase, qualitatively similar to the increase in the H-reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

The motoneurons to the Soleus muscle in the decerebrate cat were activated by the crossed extensor reflex, elicited by stimulation of the contralateral common peroneal (CP) nerve. Monosynaptic reflexes were obtained from the Soleus motoneuron pool by stimulation of the cut L7-S1 dorsal roots. The amplitude of the reflex increased approximately linearly with the recruitment level of the motoneuron pool. Tonic postsynaptic inhibition was induced in the Soleus moto-neuron pool by repetitive antidromic stimulation of the Lateral Gastrocnemius (LG) and Medial Gastrocnemius (MG) nerves at a rate of 17–47 stimuli/s. This reduced the size of the monosynaptic reflex at rest by at least 40%. However, when the motoneurons were active, the amplitude of the monosynaptic reflex obtained during repetitive stimulation of the LG-MG nerve increased with the recruitment level along the same curve as the control reflexes. Thus, tonic postsynaptic inhibition of the motoneurons per se cannot control the amplitude of the monosynaptic reflex independently of the recruitment level of the motoneuron pool. These experimental results verify predictions from computer simulations and suggest by exclusion that presynaptic inhibition is needed to control the amplitude of the monosynaptic reflex independently of the recruitment level of the motor pool.

Neural cuffs, implanted around various hindlimb nerves (sural, common peroneal, posterior tibial), were used to deliver brief stimulus trains to unrestrained cats walking on a treadmill. The resulting perturbations of the step cycle were evaluated by analyzing the EMG bursts recorded from the ankle extensors and by high speed cinematography. It was found that relatively weak stimulation (1.4 to 2 X T) of the posterior tibial nerve was very effective in eliciting a prolongation of the flexion phase provided the stimuli were applied just prior to the expected onset of the ankle extensor EMG burst. This ipsilateral hyperflexion was correlated with a prolongation of the contralateral extension. The same stimuli applied during stance usually evoked a yielding of the stimulated leg and a prolongation of the ongoing contralateral stance. In addition to these flexor and extensor reflex effects, it was found that low threshold stimulation of the sural and common peroneal nerves resulted in a powerful reflex activation of the ankle extensors. In contrast, stimulation of the gastrocnemius-soleus nerve (a muscle nerve) produced no discernible behavioral effects, even for stimuli at 3 X T, indicating that the observed reflexes are probably mediated by cutaneous afferents. The results were largely confirmed in experiments using the same cuffs implanted in spontaneously walking premammilliary cats.