Cortical control of presynaptic inhibition of Ia afferents in humans

The effect of transcranial magnetic stimulation was investigated on presynaptic inhibition of Ia terminals in the human upper and lower limb. Presynaptic inhibition of Ia afferents was assessed by three different and independent methods: (1) heteronymous Ia facilitation of the H-reflex (assessing ongoing presynaptic inhibition of Ia afferents in the conditioning volley); (2) long-lasting inhibition of the H-reflex by a group I volley (D1 inhibition, assessing presynaptic inhibition on Ia afferents in the test volley); (3) measurement of the monosynaptic Ia peak evoked in single motor units by a homonymous or heteronymous volley (post stimulus time histogram method). The first two methods were used on the lower limb; the last two on the upper limb. Provided that the corticospinal volley and the explored Ia volley were directed to the same target motoneurones, cortical stimulation evoked significant and congruent changes: (1) In the lower limb, transcranial stimulation provided increased heteronymous Ia facilitation and decreased D1 inhibition, both of which suggest a decrease in presynaptic inhibition of Ia afferents; (2) in the upper limb, transcranial stimulation provided an increase in the radial-induced inhibition of the wrist flexor H-reflex and a decrease in the peak of monosynaptic Ia excitation in single units, both of which suggest an increase in presynaptic inhibition. Selectivity of corticospinal effects was explored by testing presynaptic inhibition of Ia afferents to soleus motoneurones and focusing the transcranial stimulation to excite preferentially different motor nuclei (soleus, quadriceps and tibialis anterior). A cortical-induced decrease in presynaptic inhibition of Ia afferents was seen when, and only when, cortical and peripheral Ia volleys were directed to the same motor nucleus. Received: 18 July 1997 / Accepted: 10 November 1997     

Changes in corticospinal drive to spinal motoneurones following visuo-motor skill learning in humans

We have previously demonstrated an increase in the excitability of the leg motor cortical area in relation to acquisition of a visuo-motor task in healthy humans. It remains unknown whether the interaction between corticospinal drive and spinal motoneurones is also modulated following motor skill learning. Here we investigated the effect of visuo-motor skill training involving the ankle muscles on the coupling between electroencephalographic (EEG) activity recorded from the motor cortex (Cz) and electromyographic (EMG) activity recorded from the left tibialis anterior (TA) muscle in 11 volunteers. Coupling in the time (cumulant density function) and frequency domains (coherence) between EEG–EMG and EMG–EMG activity were calculated during tonic isometric dorsiflexion before and after 32 min of training a visuo-motor tracking task involving the ankle muscles or performing alternating dorsi- and plantarflexion movements without visual feedback. A significant increase in EEG–EMG coherence around 15–35 Hz was observed following the visuo-motor skill session in nine subjects and in only one subject after the control task. Changes in coherence were specific to the trained muscle as coherence for the untrained contralateral TA muscle was unchanged. EEG and EMG power were unchanged following the training. Our results suggest that visuo-motor skill training is associated with changes in the corticospinal drive to spinal motorneurones. Possibly these changes reflect sensorimotor integration processes between cortex and muscle as part of the motor learning process.     

Projections of group Ia afferents to motoneurons of thigh muscles in man

Summary Changes in the firing probability of single motor units in response to electrical stimulation of muscle nerves and to tendon taps were used to derive the projections of large muscle afferents to the motoneurons of various thigh muscles in man. Homonymous facilitation was demonstrated to virtually all of the sampled motor units of biceps (BI), semitendinosus (ST), vastus lateralis (VL) and vastus medialis (VM). Heteronymous facilitation was readily demonstrated between VM and VL but was never obtained from ST to BI and never unequivocally obtained from BI to ST. Reciprocal inhibition was demonstrated from femoral nerve afferents to all of the sampled units of BI, and ST but reciprocal inhibition of VM or VL was never obtained from BI afferents and infrequently from ST afferents. These projections of group I afferents in man show certain specific differences from those of the cat and baboon that may reflect the normal function of the limb.     

Responses of Ia and spindle group II afferents to single motor-unit contractions

1. The responses of deefferented Ia and spindle group II afferents to electrically activated twitch contractions of randomly selected motor units of the cat tibialis posterior muscle have been studied. Each afferent was paired with from 8 to 20 of the muscle's 60 motor units, and each afferent-motor unit interaction was recorded to two muscle lengths. 2. Cross-correlation histograms were compiled for each afferent-motor unit interaction studied as well as the average twitch tension produced by the motor unit. A numerical "coupling index" was computed for the histogram distributions to quantitate the extent of mechanical coupling between the receptor and the single motor units. 3. Qualitatively, no consistent differences were noted in the responses of Ia and spindle group II afferents to single motor-unit contractions. However, Ia afferents were responsive to a higher percentage of motor units with which they were tested (89%) and, on the average, displayed a significantly larger magnitude of response (mean coupling index, 0.72 +/- 0.04 SE) than the spindle group II afferents (66% of motor units; mean coupling index, 0.51 +/- 0.03). 4. The extent to which a motor-unit contraction altered the discharge pattern of a spindle afferent was not strictly related to the amount of force generated by the unit, nor to its contraction time. 5. Muscle length exerted a strong influence on both the qualitative and quantitative features of many of the motor unit-muscle receptor interactions. 6. These results suggest that the degree of "mechanical coupling" between a receptor and a motor unit is largely dependent on anatomical arrangements and reinforce the possibility that muscle receptors generate a "sensory partitioning" of the motor-unit population within a muscle.     

Absence of effects of contralateral group I muscle afferents on presynaptic inhibition of Ia terminals in humans and cats

Crossed effects from group I afferents on reflex excitability and their mechanisms of action are not yet well understood. The current view is that the influence is weak and takes place indirectly via oligosynaptic pathways. We examined possible contralateral effects from group I afferents on presynaptic inhibition of Ia terminals in humans and cats. In resting and seated human subjects the soleus (SO) H-reflex was conditioned by an electrical stimulus to the ipsilateral common peroneal nerve (CPN) to assess the level of presynaptic inhibition (PSI_control). A brief conditioning vibratory stimulus was applied to the triceps surae tendon at the contralateral side (to activate preferentially Ia muscle afferents). The amplitude of the resulting H-reflex response (PSI_conditioned) was compared to the H-reflex under PSI_control, i.e., without the vibration. The interstimulus interval between the brief vibratory stimulus and the electrical shock to the CPN was -60 to 60 ms. The H-reflex conditioned by both stimuli did not differ from that conditioned exclusively by the ipsilateral CPN stimulation. In anesthetized cats, bilateral monosynaptic reflexes (MSRs) in the left and right L(7) ventral roots were recorded simultaneously. Conditioning stimulation applied to the contralateral group I posterior biceps and semitendinosus (PBSt) afferents at different time intervals (0-120 ms) did not have an effect on the ipsilateral gastrocnemius/soleus (GS) MSR. An additional experimental paradigm in the cat using contralateral tendon vibration, similar to that conducted in humans, was also performed. No significant differences between GS-MSRs conditioned by ipsilateral PBSt stimulus alone and those conditioned by both ipsilateral PBSt stimulus and contralateral tendon vibration were detected. The present results strongly suggest an absence of effects from contralateral group I fibers on the presynaptic mechanism of MSR modulation in relaxed humans and anesthetized cats.     

Recurrent inhibition of interneurones monosynaptically activated from group Ia afferents

1. Interneurones monosynaptically excited from large muscle spindle (Ia) afferents and inhibited from motor axon collaterals were searched for in the lumbar spinal cord of the cat.2. Monosynaptic Ia excitation was found in sixty-seven of sixty-nine interneurones inhibited by antidromic volleys. These interneurones were excited from Ia afferents from one or a few muscles (mainly close synergists). Volleys in high threshold muscle and skin afferents (FRA) evoked polysynaptic excitation or inhibition. Weak inhibition from Ia afferents (from antagonists to those giving Ia excitation) was seen in a few cells. Monosynaptic excitation was evoked from the ventral quadrant of the spinal cord and polysynaptic excitation from the dorsal quadrant.3. Inhibition from motor axon collaterals was evoked with a latency (1.2-2.0 msec) suggesting a disynaptic linkage and had the same time course as in motoneurones. It prevented synaptic activation of 60% of interneurones and decreased the firing index and delayed generation of spikes in the remaining.4. The interneurones with convergence of monosynaptic Ia excitation and inhibition from motor axon collaterals were found in the ventral horn dorsomedial to motor nuclei. No inhibition by antidromic volleys could be detected in interneurones located in intermediate nucleus and activated monosynaptically from Ia, Ib, group I or cutaneous afferents.5. It was concluded that the ventral Ia interneurones inhibited by volleys in recurrent motor axon collaterals mediate the reciprocal Ia inhibition to motoneurones.     

Alterations in group Ia projections to motoneurons following spinal lesions in humans

1. The hypothesis that the exaggerated tendon jerks and stretch reflexes that follow chronic spinal cord lesions in humans result from alterations in transmission from group I muscle afferents to motoneurons was tested by making observations on nine normal subjects and 25 patients with spinal cord lesions. All the patients had increased tendon jerks, one-third of them had both increased tendon jerks and increased, velocity-dependent stretch reflexes (i.e.g spasticity). 2. Changes in the firing probability of single, voluntary-activated soleus or tibialis anterior motor units during stimulation of the muscle nerve below the threshold of the alpha-motoneuron axons were used to derive the characteristics of the postsynaptic potentials produced by group I volleys in single motoneurons. Paired stimuli were used to test how multiple volleys in group I muscle afferents were transmitted to motoneurons. 3. Stimulation of the posterior tibial nerve produced a short-latency period of increased firing probability representing the homonymous composite Ia excitatory postsynaptic potential (EPSP) in all soleus motoneurons tested. There was no detectable alteration in the magnitude, duration, or profile of the short-latency facilitation in the patients with spinal lesions when compared with normal subjects. 4. In patients with traumatic spinal cord lesions less than 8 wk in duration the magnitude of the facilitation representing the composite Ia EPSP was significantly larger than normal, although only one out of the four patients in this group had spasticity. 5. In the patients with the greatest spasticity, group I volleys produced a second period of facilitation 11-15 ms after the facilitation representing the composite Ia EPSP. This is presumed to represent enhanced transmission through polysynaptic pathways from group I afferents to motoneurons. 6. In normal subjects the facilitation of motoneurons produced by the second of two group I volleys is greater 5 and 10 ms after the first volley and less 20, 30, and 50 ms after the first volley. These changes involve at least two factors: 1) changes in excitability of peripheral nerves and 2) changes in transmission at the Ia-motoneuron synapse. 7. In patients with spinal lesions the facilitation produced by the second of two muscle-afferent volleys was less depressed at the 30-ms interstimulus interval. 8. Thus two separate abnormalities have been uncovered in human subjects with chronic spinal lesions: 1) a change in the transmission of multiple volleys from muscle afferents to motoneurons and 2) an increase in transmission through polysynaptic pathways from Ia afferents to motoneurons. Both could contribute to the increased tendon jerks and exaggerated stretch reflexes.     

Presynaptic inhibition of excitatory afferents to hilar mossy cells

The hippocampus contains one very strong recurrent excitatory network formed by associational connections between CA3 pyramidal cells and another that depends largely on a disynaptic excitatory pathway between dentate granule cells. The recurrent excitatory network in CA3 has long been considered a possible location of autoassociative memory storage, whereas changes in the level and arrangement of recurrent excitation between granule cells are strongly implicated in epileptogenesis. Hilar mossy cells are likely to receive collateral input from CA3 pyramidal cells and they are key intermediaries (by mossy fiber inputs) in the recurrent excitatory network between granule cells. The current study uses minimal stimulation techniques in an in vitro preparation of the rat dentate gyrus to examine presynaptic modulation of both mossy fiber and non-mossy fiber inputs to hilar mossy cells. We report that both mossy fiber and non-mossy fiber inputs to hilar mossy cells express presynaptic gamma-aminobutyric acid type B (GABA(B)) receptors that are subject to tonic inhibition by ambient GABA. We further find that only non-mossy fiber inputs express presynaptic muscarinic acetylcholine receptors, but that bath application of cholinergic agonists produces action potential-dependent increases in ambient GABA that can indirectly inhibit mossy fiber inputs. Finally, we demonstrate that mossy cells express high-affinity postsynaptic GABA(A) receptors that are also capable of detecting changes in ambient GABA produced by cholinergic agonists. Our results are among the first to directly characterize these important collateral inputs to hilar mossy cells and may help facilitate informed comparison between primary and collateral projections in two major excitatory pathways.     

Spinal opioid receptor-sensitive muscle afferents contribute to the fatigue-induced increase in intracortical inhibition in healthy humans

We investigated the influence of spinal opioid receptor-sensitive muscle afferents on cortical changes following fatiguing unilateral knee-extensor exercise. On separate days, seven subjects performed an identical five sets of intermittent isometric right-quadriceps contractions, each consisting of eight submaximal contractions [63 ± 7% maximal voluntary contraction (MVC)] and one MVC. The exercise was performed following either lumbar interspinous saline injection or lumbar intrathecal fentanyl injection blocking the central projection of spinal opioid receptor-sensitive lower limb muscle afferents. To quantify exercise-induced peripheral fatigue, quadriceps twitch force (Q(tw,pot)) was assessed via supramaximal magnetic femoral nerve stimulation before and after exercise. Motor evoked potentials and cortical silent periods (CSPs) were evaluated via transcranial magnetic stimulation of the motor cortex during a 3% MVC pre-activation period immediately following exercise. End-exercise quadriceps fatigue was significant and similar in both conditions (Q(tw,pot) -35 and -39% for placebo and fentanyl, respectively; P = 0.38). Immediately following exercise on both days, motor evoked potentials were similar to those obtained prior to exercise. Compared with pre-exercise baseline, CSP in the placebo trial was 21 ± 5% longer postexercise (P < 0.01). In contrast, CSP following the fentanyl trial was not significantly prolonged compared with the pre-exercise baseline (6 ± 4%). Our findings suggest that the central effects of spinal opioid receptor-sensitive muscle afferents might facilitate the fatigue-induced increase in CSP. Furthermore, since the CSP is thought to reflect inhibitory intracortical interneuron activity, which may contribute to central fatigue, our findings imply that spinal opioid receptor-sensitive muscle afferents might influence central fatigue by facilitating intracortical inhibition.     

The effect of baclofen and diazepam on motor skill acquisition in healthy subjects

Antispastic medication is often used in the clinic together with physiotherapy. However, some of the antispastic drugs, e.g., baclofen and diazepam, may influence the plastic mechanisms that are necessary for motor learning and hence efficient physiotherapy. In the present study, we consequently investigated the influence of baclofen and diazepam on acquisition of a visuomotor skill. The study was designed as a semi-randomized, double-blinded, placebo-controlled, crossover study in 16 healthy human subjects. The motor skill task required the subjects to match a given force trajectory by increasing or decreasing ankle dorsiflexor torque. Subjects trained for a total of 30 min. Transcranial magnetic stimulation of the primary motor cortex leg area was applied to elicit motor evoked potentials in the anterior tibial muscle (TA). Coupling between populations of TA motor units was calculated in the frequency (coherence) domain during isometric dorsiflexion. Subjects receiving placebo showed statistically significant improvement in motor performance (q = 34.1, P = 0.014) accompanied by a statistically significant reduction in intramuscular coherence. Subjects receiving baclofen and diazepam conversely showed no progression in motor performance (P > 0.05), and the training was not accompanied by a decrease in intramuscular coherence. TA motor evoked potentials had significantly lower threshold following the training in the placebo group, whereas this was not the case in the treatment groups. These data indicate that diazepam and baclofen interfere with the acquisition of a motor skill by disrupting some of the neuroplastic changes that are involved in improved motor performance. This suggests that antispastic treatment should be used with caution in subjects receiving concomitant physiotherapy.     

Specific and nonspecific mechanisms involved in generation of PAD of group Ia afferents in cat spinal cord

In the spinal cord of the anesthetized cat, we measured the changes in extracellular concentration of potassium ions [K+]e and the negative DC shifts produced by stimulation of muscle, cutaneous and mixed afferent nerves, together with alterations in the threshold of single group Ia fibers that were tested at the same site as the potassium measurements. This approach provided information on the extent to which the excitability changes of single Ia-fibers can be correlated with the changes in [K+]e occurring at the same site. Stimulation of the tibial (TIB) nerve and of the cutaneous sural (SU), and superficial peroneous (SP) nerve (100-Hz trains lasting 30-60 s) with stimulus strengths of 10-15 times threshold increased the concentration of [K+]e in the dorsal horn by 2-5 mmol/l above the resting value of 3 mmol/l. This was in clear contrast with the very small [K+]e increases produced at the same site during stimulation of muscle nerves, such as the posterior biceps and semitendinosus (PBSt), gastrocnemius soleus (GS), and deep peroneus (DP), which were generally smaller than 0.25 mmol/l. Stimulation of the PBSt and GS muscle nerves did produce small, but clear, increases of [K+]e (up to 0.3 mmol/l) in the region of the intermediate nucleus, where these fibers synapse with second order cells. These changes were nevertheless smaller than those produced at the same site by stimulation of the TIB, SU, and SP nerves. The peak amplitudes of the [K+]e transients produced by long-lasting 100-Hz trains applied to cutaneous and/or to muscle nerves showed a linear relationship with the amplitudes of the slow negative DC shifts, which were simultaneously recorded from the NaCl barrel of the potassium electrode assembly. Stimulus trains (100 Hz) applied to group I muscle afferents (PBSt and DP) very effectively reduced the threshold for intraspinal activation of individual group I GS fibers but produced negligible negative DC shifts at the same site. On the other hand, 100-Hz stimulus trains applied to the SU and SP nerves produced large negative DC shifts, even with low-stimulus strengths (2 X T, where T is threshold), but had much smaller effects on the threshold of group Ia GS fibers. Increasing the intensity of the stimuli applied to cutaneous and mixed nerves above 2 X T strength further reduced the threshold of the Ia-fibers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Contribution of group III and IV muscle afferents to multisensorial spinal motor control in cats

The contribution of group III and IV muscle afferents to multisensorial segmental reflex pathways was investigated by testing for spatial facilitation between these afferents and non-nociceptive segmental afferents from skin, muscles and joints on postsynaptic potentials (PSPs) in alpha-motoneurones recorded in anaemically decapitated high spinal cats. Group III and IV muscle afferents were activated by intraarterial injection of potassium chloride (320 mM) or bradykinin triacetate (81 microM). Skin, joint and group I-II muscle afferents were stimulated by graded electrical stimulation of various nerves. Conditioning by stimulation of group III and IV muscle afferents spatially facilitated the transmission in segmental reflex pathways from low- to medium-threshold cutaneous and joint afferents as well as from lb and group II muscle afferents. Both excitatory and inhibitory pathways from these afferents were facilitated. Monosynaptic excitation and disynaptic antagonistic inhibition from group Ia afferents remained unaffected. It is concluded that the spatial facilitation observed between group III and IV muscle afferents and the other afferents indicate a convergence from group III and IV muscle afferents and the other afferents on common interneurones in segmental flexor reflex pathways. Under physiological conditions they thus contribute to the multisensorial feedback of the flexor reflex pathways. Pathophysiologically, the observed convergence may aggravate muscle weakness and atrophy of muscles induced by group III and IV muscle afferents.     

The pathway from Ia forelimb afferents to the motor cortex: a new hypothesis.

Forelimb target-reaching and food-taking in cats depend on different interneuronal circuitry in the spinal cord. On the basis of previous findings regarding the effect of transection of the corticospinal tract in the spinal cord, of high dorsal column (DC) transection, of low pyramidotomy and of pyramidotomy after previous DC transection, it is proposed that the food-taking movement is temporally linked to target-reaching as follows: During target-reaching, the position of the paw is signalled by the pathway from forelimb proprioceptors (mainly Ia) to the motor cortex with a relay in the main cuneate nucleus. The command for food-taking is issued by the motor cortex only when the pathway from the forelimb signals that the paw approaches the target correctly, as may be determined by a comparison of the information from the forelimb with an efference copy of the motor program for target-reaching. The hypothesis is based on previous results regarding the organization of the pathway from the forelimb to area 3a and the motor cortex, and regarding the cortico-cuneate pathway with selective projection from area 3a and motor cortex to the basal caudal part of the cuneate nucleus, where the proprioceptive information from the forelimb is relayed. Results relevant to the present hypothesis regarding responses of precentral neurones during active and passive movements in awake animals are briefly discussed.