Prolonged time course of population excitatory postsynaptic potentials in motoneurons of chronic stroke survivors

Hyperexcitability of spinal motoneurons may contribute to muscular hypertonia after hemispheric stroke. The origins of this hyperexcitability are not clear, but we hypothesized that prolongation of the Ia excitatory postsynaptic potential (EPSP) in spastic motoneurons may be one potential mechanism, by enabling more effective temporal summation of Ia EPSPs, making action potential initiation easier. Thus, the purpose of this study is to quantify the time course of putative EPSPs in spinal motoneurons of chronic stroke survivors. To estimate the EPSP time course, a pair of low-intensity electrical stimuli was delivered sequentially to the median nerve in seven hemispheric stroke survivors and in six intact individuals, to induce an H-reflex response from the flexor carpi radialis muscle. H-reflex response probability was then used to quantify the time course of the underlying EPSPs in the motoneuron pool. A population EPSP estimate was then derived, based on the probability of evoking an H-reflex from the second test stimulus in the absence of a reflex response to the first conditioning stimulus. Our experimental results showed that in six of seven hemispheric stroke survivors, the apparent rate of decay of the population EPSP was markedly slower in spastic compared with contralateral (stroke) and intact motoneuron pools. There was no significant difference in EPSP time course between the contralateral side of stroke survivors and control subject muscles. We propose that one potential mechanism for hyperexcitability of spastic motoneurons in chronic stroke survivors may be associated with this prolongation of the Ia EPSP time course. Our subthreshold double-stimulation approach could provide a noninvasive tool for quantifying the time course of EPSPs in both healthy and pathological conditions. NEW & NOTEWORTHY Spastic motoneurons in stroke survivors showed a prolonged Ia excitatory postsynaptic potential (EPSP) time course compared with contralateral and intact motoneurons, suggesting that one potential mechanism for hyperexcitability of spastic motoneurons in chronic stroke survivors may be associated with this prolongation of the Ia EPSP time course.

Estimating the time course of population excitatory postsynaptic potentials in motoneurons of spastic stroke survivors

Hyperexcitable motoneurons are likely to contribute to muscle hypertonia after a stroke injury; however, the origins of this hyperexcitability are not clear. One possibility is that the effective duration of the Ia excitatory postsynaptic potential (EPSP) is prolonged, increasing the potential for temporal summation of EPSPs, making action potential initiation easier. Accordingly, the purpose of this study was to quantify the time course of EPSPs in motoneurons of stroke survivors. The experimental protocol, which was based on parameters derived from simulation, involved sequential subthreshold electrical stimuli delivered to the median nerve of hemispheric stroke survivors. The resulting H-reflex responses were recorded in the flexor carpi radialis muscle. H-reflex response probability was then used to quantify the time course of the underlying EPSPs in the motoneuron pool. A population EPSP was estimated based on the probability of evoking an H reflex from the second electrical stimulus in the absence of a reflex response to the first stimulus. The accuracy of this time-course estimate was quantified using a computer simulation that explored a range of feasible EPSP parameters. Our experimental results showed that in all five hemispheric stroke survivors the rate of decay of the population EPSP was consistently slower in spastic compared with the contralateral motoneuron pools. We propose that one potential mechanism for hyperexcitability of motoneurons in spastic stroke survivors may be linked to this prolongation of the Ia EPSP time course. Our subthreshold double-stimulation approach also provides a noninvasive tool for quantifying the time course of EPSPs in both healthy and pathological conditions.

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.

Analysis of effective synaptic currents generated by homonymous Ia afferent fibers in motoneurons of the cat

1. We have developed a technique to measure the total amount of current from a synaptic input system that reaches the soma of a motoneuron under steady-state conditions. We refer to this quantity as the effective synaptic current (IN) because only that fraction of the synaptic current that actually reaches the soma and initial segment of the cell affects its recruitment threshold and firing frequency. 2. The advantage of this technique for analysis of synaptic inputs in comparison to the standard measurements of synaptic potentials is apparent from Ohm's law. Steady-state synaptic potentials recorded at the soma of a cell are the product of IN and input resistance (RN), which is determined by intrinsic cellular properties such as cell size and membrane resistivity. Measuring IN avoids the confounding effect of RN on the amplitudes of synaptic potentials and thus provides a more direct assessment of the magnitude of a synaptic input. 3. Steady-state synaptic inputs were generated in cat medial gastrocnemius (MG) motoneurons by using tendon vibration to activate homonymous Ia afferents. We found that the magnitude of the Ia effective synaptic current (Ia IN) was not the same in all MG cells. Instead, Ia IN covaried with RN (r = 0.64; P less than 0.001), being about twice as large on average in motoneurons with high RN values as in those with low RN values. Ia IN was also correlated with motoneuron rheobase, afterhyperpolarization duration, and axonal conduction velocity. 4. A comparison of transient Ia EPSPs with steady-state Ia EPSPs (Ia EPSPSS) evoked in the same cells suggested that the effective synaptic current that produces the transient Ia EPSP was also greater in motoneurons with high RN values than in those with low RN values. 5. The factors responsible for the Ia IN-RN covariance are uncertain. However, our finding greater values of Ia IN in high RN motoneurons is consistent with other evidence suggesting that Ia boutons on these motoneurons have a higher probability for neurotransmitter release than those on low RN motoneurons (19). 6. The neural mechanisms underlying orderly recruitment are discussed. The effect of the Ia input is to produce an approximately twofold expansion of the differences in motoneuron recruitment thresholds that are generated by intrinsic cellular properties. It is suggested that the higher efficacy of Ia input in low-threshold motoneurons confers particular importance on this input system in the control of vernier movements (7).

Amino acid receptor-mediated transmission at primary afferent synapses in rat spinal cord

Intracellular recording techniques have been used to provide information on the identity of excitatory transmitters released at synapses formed between dorsal root ganglion (DRG) and spinal cord neurones in two in vitro preparations. Explants of embryonic rat DRG were added to dissociated cultures of embryonic dorsal horn neurones and synaptic potentials recorded intracellularly from dorsal horn neurones after DRG explant stimulation. More than 80% of dorsal horn neurones received at least one fast, DRG-evoked, monosynaptic input. In the presence of high divalent cation concentrations (5 mmol l-1 Ca2+, 3 mmol l-1 Mg2+) the acidic amino acid receptor agonists, L-glutamate, kainate (KA) and quisqualate (QUIS) excited all dorsal horn neurones which received a monosynaptic DRG neurone input, whereas L-aspartate and N-methyl-D-aspartate (NMDA) had little or no action. 2-Amino-5-phosphonovalerate (APV), a selective NMDA receptor antagonist, was relatively ineffective at antagonizing DRG-evoked synaptic potentials and L-glutamate-evoked responses. In contrast, kynurenate was found to be a potent antagonist of amino acid-evoked responses and of synaptic transmission at all DRG-dorsal horn synapses examined. The blockade of synaptic transmission by kynurenate appeared to result from a postsynaptic action on dorsal horn neurones. Intracellular recordings from motoneurones in new-born rat spinal cord were used to study the sensitivity of the Ia excitatory postsynaptic potential (EPSP) to antagonists of excitatory amino acids. Superfusion of the spinal cord with APV did not inhibit the Ia EPSP but did suppress later, polysynaptic components of the afferent-evoked response. Kynurenate was a potent and selective inhibitor of the Ia EPSP, acting via a postsynaptic mechanism. These findings indicate that L-glutamate, or a glutamate-like compound, but not L-aspartate, is likely to be the predominant excitatory transmitter that mediates fast excitatory postsynaptic potentials at primary afferent synapses with both dorsal horn neurones and motoneurones.

Reversibility of Ia EPSP investigated with intracellularly iontophoresed QX-222

1. Cat lumbosacral motoneurons were impaled by two individually advanced microelectrodes: one to record membrane potential (EM), the second to pass depolarizing currents. 2. During the passage of depolarizing current ramps the repetitive action-potential firing and the later high conductance (GM) state obscured and distorted Ia excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of hindlimb muscle afferents. 3. Intracellular iontophoresis of QX-222 (a trimethyl analogue of lignocaine) or methylxylocholine, prevented action-potential generation and reduced the GM increase during current depolarization so that positive levels of EM could be reached. 4. Following QX-222 treatment it was possible to demonstrate a reversal of the Ia EPSP including its first part, at EM values between -13 and +32 mV. Reversal was seen in 13 of the 22 motoneurons tested. 5. Reversal was easiest to obtain in motoneurons of the deep peroneal group. More positive levels of EM were needed to show a reversal in neurons of the gastrocnemius-so-leus group. (The 10-90% rise times of the EPSPs were rather similar for both groups.) 6. In a few motoneurons the initial part of the Ia EPSP reversed at a more negative EM than a later part. This was best seen after subtraction of the extracellular field potentials from the records.

Synaptic organization of defined motor-unit types in cat tibialis anterior

1. Synaptic potentials were recorded intracellularly in tibialis anterior (TA) motoneurons following stimulation of a descending brain stem pathway, the medial longitudinal fasciculus (MLF), and three segmental inputs, the homonymous and heteronymous group Ia afferents, the group I afferents from the antagonist, and the cutaneous and muscle afferents. Intracellular stimulation of the motoneurons was used to classify them, based on the properties of the innervated muscle units, into types FF, F(int), FR, and S (6, 16). 2. The sum of the monosynaptic EPSP amplitudes resulting from stimulation of homonymous and heteronymous group Ia afferents (summed group Ia EPSP) was inversely related to motoneuron size, as assessed by motoneuron input resistance, and was inversely related to motor-unit tetanic tension. Type-FF, -FR, and -S motoneurons showed significant differences in the mean amplitude of their summed group Ia EPSPs. 3. The amplitudes of disynaptic IPSPs resulting from stimulation of group I afferents in the antagonist muscle also showed an inverse relationship to motoneuron size. The observed relationships between motoneuron size and the monosynaptic group Ia EPSP amplitude or the disynaptic group I IPSP amplitude are compatible with the “size principle” of motor-unit recruitment (26). 4. The amplitudes of the monosynaptic EPSPs evoked in TA motoneurons by stimulation of the MLF were distributed rather randomly among all types of TA motoneurons. A slight tendency of larger monosynaptic EPSPs to occur in motoneurons with larger tetanic tensions was observed. 5. The polysynaptic effects from cutaneous and muscle afferents in sural and gastrocnemius-soleus nerves were frequently excitatory on type-FF motoneurons, but were primarily inhibitory on type-FR and -S motoneurons. Clearly, the polysynaptic cutaneous and muscle inputs and the monosynaptic MLF input onto TA motoneurons show a different pattern of synaptic organization than the group I inputs. 6. In general, the synaptic organization of the TA motor nucleus is similar to that of its extensor antagonist, medial gastrocnemius (MG) (2--5, 7, 8), when analogous neural circuits are compared. This parallel organization suggests a commonality of motor-control systems for both flexor and extensor muscles.