Plastic Spinal Motor Circuits in Health and Disease.

In the past, the spinal cord was considered a hard-wired network responsible for spinal reflexes and a conduit for long-range connections. This view has changed dramatically over the past few decades. It is now recognized as a plastic structure that has the potential to adapt to changing environments. While such changes occur under physiological conditions, the most dramatic alterations take place in response to pathological events. Many of the changes that occur following such pathological events are maladaptive, but some appear to help adapt to the new conditions. Although a number of studies have been devoted to elucidating the underlying mechanisms, in humans and animal models, the etiology and pathophysiology of various diseases impacting the spinal cord are still not well understood. In this review, we summarize current understanding and outstanding challenges for a number of diseases, including spinal muscular atrophy (SMA), amyotrophic laterals sclerosis (ALS), and spinal cord injury (SCI), with occasional relations to stroke. In particular, we focus on changes resulting from SCI (and stroke), and various influencing factors such as cause, site and extent of the afflicted damage.

Is the stabilization of quiet upright stance in humans driven by synchronized modulations of the activity of medial and lateral gastrocnemius muscles?

A matrix of 120 electromyogram (EMG) electrodes (8 rows and 15 columns) was used to investigate individual activation patterns of the medial (MG) and lateral gastrocnemius (LG) muscles during forward sways of the body in human quiet stance. This matrix was positioned on the right calf of eight subjects after identification of the MG and LG contours with ultrasound scanning. Gray-scale images were generated with the maxima and minima of the cross-correlation function between the envelope of each EMG signal and the body center of pressure (CoP) for individual forward sways. These images were automatically segmented to reduce the data set into representative and local values of EMG-CoP cross-correlation for each muscle. On average, modulations in EMG amplitude preceded the onset of forward sways with a variable timing, with both gastrocnemius muscles being similarly and synchronously modulated in 193 out of 236 sways. Variations in the timing of activation between muscles were less frequent, although consistent across subjects and significantly correlated with changes in the direction and velocity of body sways. Interestingly, the time shift between EMG and CoP traces sometimes varied consistently along different channels of the same column of electrodes, either in proximal-to-distal or distal-to-proximal direction. The variable EMG-CoP cross-correlation delay was not congruent with the delay expected for the propagation of surface potentials along muscle fibers. Comparison of surface EMGs with intramuscular EMGs recorded from six subjects demonstrated that surface potentials provide high spatial selectivity, thus supporting the notion of selective activation of motor units during quiet standing. Hence, the stabilization of the quiet standing posture likely relies on flexible rather than stereotyped mechanisms of control.

Muscle spindles are multi-functional.

The number and distribution of mammalian muscle spindles in their parent muscle are not simply related to overall muscle length because (i) they lie in parallel to muscle-fibers in series to elastic elements; (ii) muscle architectures are complex and may be functionally partitioned; (iii) task-dependent fusimotor inputs co-determine spindle firing and (iv) the complex central connectivity co-determines the functional use made of spindle afferent signals. Muscle spindles are multi-functional.

Effects of spinal recurrent inhibition on motoneuron short-term synchronization.

Spinal recurrent inhibition linking skeleto- motoneurons (alpha-MNs) via Renshaw cells (RCs) has been variously proposed to increase or decrease tendencies toward synchronous discharges between alpha-MNs. This controversy is not easy to settle experimentally in animal or human paradigms because RCs receive, in addition to excitatory input from alpha-MNs, many other modulating influences which may change their mode of operation. Computer simulations help to artificially isolate the recurrent inhibitory circuit and thus to study its effects on alpha-MN synchronization under conditions not achievable in natural experiments. We present here such a study which was designed to specifically test the following hypothesis. Since many alpha-MNs excite any particular Renshaw cell, which in turn inhibits many alpha-MNs, this convergence-divergence pattern establishes a random network whose random discharge patterns inject uncorrelated noise into alpha-MNs, and this noise counteracts any synchronization potentially arising from other sources, e.g., common inputs (Adam et al. in Biol Cybern 29:229-235, 1978). We investigated the short-term synchronization of alpha-MNs with two types of excitatory input signals to alpha-MNs (random and sinusoidally modulated random patterns). The main results showed that, while recurrent inhibitory inputs to different alpha-MNs were indeed different, recurrent inhibition (1) exerted rather small effects on the modulation of alpha-MN discharge, (2) tended to increase the short-term synchronization of alpha-MN discharge, and (3) did not generate secondary peaks in alpha-MN-alpha-MN cross-correlograms associated with alpha-MN rhythmicity.

Movement-dependent positioning errors in human elbow joint movements.

Healthy adult humans performed elbow movements in a horizontal plane under a small external extending torque (2.1-3.3 Nm). Test movements (TMs) consisted of slow ramp-and-hold flexions in the absence of visual feedback, with the target joint angle to be remembered from a preceding conditioning movement (CM). The CM was produced by matching two beams on the monitor screen: (1) command representing the target position (a straight line); and (2) a signal from the sensor of the elbow joint angle. Two kinds of CM were applied, which had the same target position (50 degrees in most experiments) but differed in initial positions: (1) fully extended joint (0 degrees, P1 CMs); (2) flexed joint (100 degrees, P2 CMs). In a group of 25 subjects, the target in TMs was usually overshot, with the position errors depending on the CMs: 2.7 +/- 0.6 degree (mean +/- SEM) for P1 CMs, and 10.9 +/- 0.7 degree (P < 0.001) for P2 CMs. Vibration of the elbow flexors substantially diminished the difference between the position errors, amounting to--0.31 +/- 0.5 degree and 2.33 +/- 0.6 degrees, respectively. It is suggested that the observed position errors resulted from after-effects in the activity of muscle spindles in agonist and antagonist muscles, but influence of differences in dynamic components of the afferent signals during oppositely directed approaches to the target cannot be excluded.

Capsaicin-induced effects on c-fos expression and NADPH-diaphorase activity in the feline spinal cord.

The distribution of c-fos expression and NADPH-diaphorase reactivity in the cervical and lumbar segments after stimulation of the vanilloid receptors in the dorsal neck muscles with capsaicin was studied in cats anaesthetized with alpha-chloralose. After the unilateral intramuscular injection of capsaicin, the mean number of Fos-immunoreactive neurons detected with an avidin-biotin-peroxidase technique was significantly increased in the superficial laminae (I), neck of the dorsal horn (V), and area around the central canal (VII) within both the cervical and lumbar spinal cord. Most Fos-immunoreactive neurons in the cervical spinal cord were giant and small cells. The widespread distribution of Fos-immunoreactive cells throughout the cervical cord within the intermediate zone (VII) coincided with the sites of localization of last-order premotor interneurons and cells of origin of inter-segmental crossed and uncrossed descending propriospinal pathways to the lumbar spinal cord. Fos-immunoreactive neurons were co-distributed with nitric oxide-generating cells at both levels of the spinal cord, although the double-labeled cells were not observed. In conclusion, the analysis of c-fos expression and NADPH-diaphorase reactivity shows that stimulation of vanilloid receptors in the neck muscles can initiate distinctive neuronal plasticity in the cervical (C1-C8) and lumbar (L1-L7) segments, and confirms the anatomical and functional coupling of both regions during processing of nociceptive signals from the dorsal neck muscles.

Effects in feline gastrocnemius-soleus motoneurones induced by muscle fatigue.

Responses of gastrocnemius-soleus (G-S) motoneurones to stretches of the homonymous muscles were recorded intracellularly in decerebrate cats before, during and after fatiguing stimulation (FST) of G-S muscles. Ventral roots (VR) L7 and S1 were cut, and FST was applied to VR S1, a single FST session including 4 to 5 repetitions of 12-s periods of regular 40 s(-1) stimulation. Muscle stretches consisted of several phases of slow sinusoidal shortening-lengthening cycles and intermediate constant lengths. The maximal stretch of the muscles was 8.8 mm above the rest length. Effects of FST on excitatory postsynaptic potentials (EPSPs) and spikes evoked by the muscle stretches were studied in 12 motoneurones from ten experiments. Stretch-evoked EPSPs and firing were predominantly suppressed after FST, with the exception of a post-contraction increase of the first EPSP after FST, which was most likely due to after-effects in the activity of muscle spindle afferents. The post-fatigue suppression of EPSPs and spike activity was followed by restoration within 60-100 s. Additional bouts of FST augmented the intensity of post-fatigue suppression of EPSPs, with the spike activity sometimes disappearing completely. FST itself elicited EPSPs at latencies suggesting activation of muscle spindle group Ia afferents via stimulation of beta-fibres. The suppression of the stretch-evoked responses most likely resulted from fatigue-evoked activity of group III and IV muscle afferents. Presynaptic inhibition could be one of the mechanisms involved, but homosynaptic depression in the FST-activated group Ia afferents may also have contributed.

Fatigue-related depression of the feline monosynaptic gastrocnemius-soleus reflex.

In decerebrate cats, changes in the monosynaptic reflex (MSR) of gastrocnemius-soleus (G-S) motoneurones were studied after fatiguing stimulation (FST) of the G-S muscles. Monosynaptic reflexes were evoked by stimulation of Ia fibres in the G-S nerve and recorded from a filament of ventral root (VR) L7. FST (intermittent 40 s(-1) stimulation for 10-12 min) was applied to the distal part of the cut VR S1. FST reduced MSR amplitudes to 0.64 +/- 0.04 (mean +/-s.e.m.) of the prefatigue values. The suppression remained stable for approximately 25 min and then MSR amplitudes gradually returned towards the normal. To test for the involvement of presynaptic and recurrent inhibition, MSRs were conditioned by stimulation of the nerve to the posterior biceps and semitendinosus (PBSt) muscles or a filament of VR L7, respectively. The intensity of presynaptic inhibition (reduction of the normalized value of MSR amplitude during conditioning) increased from 0.19 +/- 0.02 in prefatigue to 0.44 +/- 0.04 within a 5.3-18.2 min interval after FST, followed by a recovery. In contrast, the intensity of recurrent inhibition first diminished from 0.23 +/- 0.02 in prefatigue to 0.15 +/- 0.01 within 15.6-30.1 min after FST and then gradually recovered. Both primary afferent depolarization and the intensity of antidromic discharges in primary afferents increased with the presynaptic inhibition intensity. These results demonstrate a fatigue-related suppression of Ia excitation of synergistic motoneurones, probably arising from the activation of group III and IV afferents. The effects could in part be due to increased presynaptic inhibition, while recurrent inhibition plays a minor role.

Static and dynamic input-output relations of the feline medial gastrocnemius motoneuron-muscle system subjected to recurrent inhibition: a model study.

The physiological function of spinal recurrent inhibition is still a matter of debate because of the experimental difficulty or impossibility of observing recurrent inhibition at work in normally behaving animals. The purpose of this study was to investigate, by computer simulation, the role of recurrent inhibition in shaping the input-output (I/O) relationships between descending command signals (DCS) as inputs and motoneuron (MN) and Renshaw cell (RC) firing rates and muscle force as outputs. Changing the spatial (topographical) distribution of recurrent inhibition from nonhomogeneous (as in the standard model) to homogeneous did not alter the I/O relationships significantly, while changing the functional distribution related to MN types did. Altering the global gain of recurrent inhibition, as happens naturally in various motor acts, changes the slopes and positions (at high inputs) of the I/O relationships, making recurrent inhibition a suitable means of gain control. Coupling a decrease in recurrent inhibitory gain with an increase in DCS input, as could occur during slow dynamic contractions, would increase the MN and force gains during the act. Short dynamic ramp-and-hold DCS inputs generate MN firing patterns, to which recurrent inhibition contributes interspike-interval variability and damped oscillations, which are related to issues of tremor and its control.

A model of the feline medial gastrocnemius motoneuron-muscle system subjected to recurrent inhibition.

Recurrent inhibition in the mammalian spinal cord is complex, and its functions are not yet well understood. Skeletomotoneurons (alpha-MNs) excite, via recurrent axon collaterals, inhibitory Renshaw cells (RCs), which in turn inhibit alpha-MNs and other neurons. The anatomical and functional structure of the recurrent inhibitory network is nonhomogeneous, and the gain and filtering characteristics of RCs are modulated by inputs circumventing alpha-MNs. This complex organization is likely to play important roles for the discharge and recruitment properties of alpha-MNs. Modeling this system is a way of investigating hypothesized roles for normal functioning including muscle fatigue and different forms of physiological pathological tremor. In this paper, a detailed model including alpha-MNs, RCs, and the muscle fibers innervated by the alpha-MNs is presented. Outlines of the experimental data underlying the model and the modeling philosophy and procedure are presented. Then the behavior of a RC model is compared with experimental data reported in the literature. Model and experimental data agree well for burst responses elicited by synchronous single-pulse activation of different numbers of motor axons. In addition, the static relation between motor-axon activation rate and RC firing rate agree fairly well in model and experiment, and the same applies to the dynamic responses to step changes in motor-axon rate. The ultimate objective is to use this model in probing the role of recurrent inhibition in the control and stability of (isometric) muscular force under normal and altered conditions occurring during fatigue and muscle pain.

NADPH-diaphorase activity and c-fos expression in medullary neurons after fatiguing stimulation of hindlimb muscles in the rat.

In anaesthetised rats, Fos-immunoreactive and NADPH-diaphorase-positive neurons in the medulla and, for comparison, in the spinal cord were studied after fatiguing stimulation of the hindlimb muscles. Following both direct muscle stimulation and L5 ventral root stimulation, fatigue-related c-fos gene expression was most prominent in the dorsal horn of the ipsilateral L2-L5 segments and within the ipsilateral nucleus tractus solitarius, the caudoventrolateral and rostroventrolateral reticular nuclei, and the intermediate reticular nucleus at levels of -14.3 and -13.8 mm, and contralaterally at -13.2 mm caudal to the bregma. The order of intensity of c-fos expression was as follows: nucleus tractus solitarius>caudoventrolateral and rostroventrolateral reticular nuclei>intermediate reticular nucleus>lateral paragigantocellular nucleus. NADPH-diaphorase reactivity was changed in the following sequence: NTS>intermediate reticular nucleus lateral paragigantocellular nucleus>rostroventrolateral reticular nucleus. Fos-immunoreactive neurons were codistributed with NADPH-diaphorase-reactive cells within the dorsomedial and ventrolateral medulla, and double-staining neurons were found in the nucleus tractus solitarius, intermediate reticular nucleus and lateral paragigantocellular nucleus. The patterns of distribution of c-fos expression and NADPH-diaphorase reactivity show that afferent signals arising from fatiguing muscles may activate spinal and medullary neurons which are involved in nociceptive and cardiovascular reflex pathways. The functional role of nitric oxide (NO) in the generation of cardiovascular and somatosensory responses in the medulla during fatigue of skeletal muscles is discussed.