The contribution of fast corticospinal input to the voluntary activation of proximal muscles in normal subjects and in stroke patients

Although it is well known that the corticospinal system exerts more influence over distal (hand and fingers) than proximal (elbow and shoulder) upper limb muscles, differences in the importance of this system for voluntary activation of these muscle groups have not been demonstrated directly. Two investigations were carried out to provide a quantitative comparison of the contribution of fast corticospinal inputs to voluntary activity in proximal and distal muscles of normal subjects. The first study confirmed that the rate of increase in the amplitude of EMG responses to transcranial magnetic stimulation (TMS) with voluntary activation of the muscles was significantly greater in a hand muscle (first dorsal interosseous, 1DI) than in biceps, which was in turn greater than that for deltoid. The second study demonstrated that this result reflected a genuine difference in corticospinal influence over these muscles and was not due to differences in the pattern and type of motor unit recruitment in proximal vs distal muscles. The voluntary activation of a pair of low-threshold single motor units (SMUs) in 1DI and deltoid was compared with their response to TMS. In both muscles only a small amount of additional effort was required to recruit the second SMU; increments were typically within 1% of maximum voluntary contraction, as assessed from EMG measurements. Subjects were asked to voluntarily discharge the lower threshold SMU at a steady rate, and then the threshold of responses of this SMU and that of the second unit to TMS were determined. In 1DI, only small increments in TMS intensity above the threshold for the first SMU were required to activate the second unit [mean 1.4% maximum stimulator output (MSO), SD±1.0%, n=7 subjects]. In contrast, in deltoid a significantly greater intensity increase was needed (mean 6%, SD±1.2%, MSO n=7, P<0.001). Similar results were obtained when TMS thresholds of motor unit pairs were assessed in relaxed subjects. These experiments support the hypothesis that the fast corticospinal input that can be activated by TMS is of greater importance for the voluntary activation of hand than of shoulder muscles. This hypothesis served as a basis for testing deltoid responses in three stroke patients. In two patients smaller responses to TMS were obtained on the affected side than on the unaffected side during the production of equivalent voluntary contractions, suggesting that the patients achieved these contractions using inputs other than the fast corticospinal elements excited by TMS. Received: 9 June 1998 / Accepted: 16 June 1999     

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

 Experiments 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. Received: 2 July 1996 / Accepted: 9 October 1996     

Intrinsic and reflex stiffness in normal and spastic, spinal cord injured subjects

Mechanical changes underlying spastic hypertonia were explored using a parallel cascade system identification technique to evaluate the relative contributions of intrinsic and reflex mechanisms to dynamic ankle stiffness in healthy subjects (controls) and spastic, spinal cord injured (SCI) patients. We examined the modulation of the gain and dynamics of these components with ankle angle for both passive and active conditions. Four main findings emerged. First, intrinsic and reflex stiffness dynamics were qualitatively similar in SCI patients and controls. Intrinsic stiffness dynamics were well modeled by a linear second-order model relating intrinsic torque to joint position, while reflex stiffness dynamics were accurately described by a linear, third-order system relating half-wave rectified velocity to reflex torque. Differences between the two groups were evident in the values of four parameters, the elastic and viscous parameters for intrinsic stiffness and the gain and first-order cut-off frequency for reflex stiffness. Second, reflex stiffness was substantially increased in SCI patients, where it generated as much as 40% of the total torque variance, compared with controls, where reflex contributions never exceeded 7%. Third, differences between SCI patients and controls depended strongly on joint position, becoming larger as the ankle was dorsiflexed. At full plantarflexion, there was no difference between SCI and control subjects; in the mid-range, reflex stiffness was abnormally high in SCI patients; at full dorsiflexion, both reflex and intrinsic stiffness were larger than normal. Fourth, differences between SCI and control subjects were smaller during the active than the passive condition, because intrinsic stiffness increased more in controls than SCI subjects; nevertheless, reflex gain remained abnormally high in SCI patients. These results elucidate the nature and origins of the mechanical abnormalities associated with hypertonia and provide a better understanding of its functional and clinical implications.     

Adaptation of the walking pattern to uphill walking in normal and spinal-cord injured subjects

 Lower-limb movements and muscle-activity patterns were assessed from seven normal and seven ambulatory subjects with incomplete spinal-cord injury (SCI) during level and uphill treadmill walking (5, 10 and 15°). Increasing the treadmill grade from 0° to 15° induced an increasingly flexed posture of the hip, knee and ankle during initial contact in all normal subjects, resulting in a larger excursion throughout stance. This adaptation process actually began in mid-swing with a graded increase in hip flexion and ankle dorsiflexion as well as a gradual decrease in knee extension. In SCI subjects, a similar trend was found at the hip joint for both swing and stance phases, whereas the knee angle showed very limited changes and the ankle angle showed large variations with grade throughout the walking cycle. A distinct coordination pattern between the hip and knee was observed in normal subjects, but not in SCI subjects during level walking. The same coordination pattern was preserved in all normal subjects and in five of seven SCI subjects during uphill walking. The duration of electromyographic (EMG) activity of thigh muscles was progressively increased during uphill walking, whereas no significant changes occurred in leg muscles. In SCI subjects, EMG durations of both thigh and leg muscles, which were already active throughout stance during level walking, were not significantly affected by uphill walking. The peak amplitude of EMG activity of the vastus lateralis, medial hamstrings, soleus, medial gastrocnemius and tibialis anterior was progressively increased during uphill walking in normal subjects. In SCI subjects, the peak amplitude of EMG activity of the medial hamstrings was adapted in a similar fashion, whereas the vastus lateralis, soleus and medial gastrocnemius showed very limited adaptation during uphill walking. We conclude that SCI subjects can adapt to uphill treadmill walking within certain limits, but they use different strategies to adapt to the changing locomotor demands. Received: 10 March 1998 / Accepted: 29 December 1998     

Initiating extension of the lower limbs in subjects with complete spinal cord injury by epidural lumbar cord stimulation

We provide evidence that the human spinal cord is able to respond to external afferent input and to generate a sustained extension of the lower extremities when isolated from brain control. The present study demonstrates that sustained, nonpatterned electrical stimulation of the lumbosacral cord—applied at a frequency in the range of 5–15 Hz and a strength above the thresholds for twitches in the thigh and leg muscles—can initiate and retain lower-limb extension in paraplegic subjects with a long history of complete spinal cord injury. We hypothesize that the induced extension is due to tonic input applied by the epidural stimulation to primary sensory afferents. The induced volleys elicit muscle twitches (posterior root muscle-reflex responses) at short and constant latency times and coactivate the configuration of the lumbosacral interneuronal network, presumably via collaterals of the primary sensory neurons and their connectivity with this network. We speculate that the volleys induced externally to the lumbosacral network at a frequency of 5–15 Hz initiate and retain an extension pattern generator organization. Once established, this organization would recruit a larger population of motor units in the hip and ankle extensor muscles as compared to the flexors, resulting in an extension movement of the lower limbs. In the electromyograms of the lower-limb muscle groups, such activity is reflected as a characteristic spatiotemporal pattern of compound motor-unit potentials.Abbreviations C Cervical - CMUP Compound motor-unit potential - EMG Potential - CNS Central nervous system - EMG Electromyography, electromyographic - H Hamstring - L Lumbar - MLR Mesencephalic locomotor region - PARA Paraspinal muscles - Q Quadriceps - S Sacral - SCI Spinal cord injury, spinal cord-injured - SCS Spinal cord stimulation - T Thoracic - TA Tibialis anterior - TS Triceps surae     

Activity-dependent development of cortical axon terminations in the spinal cord and brain stem

 Corticospinal (CS) axon terminations in several species are widespread early in development but are subsequently refined into a spatially more restricted distribution. We studied the role of neural activity in sensorimotor cortex in shaping postnatal development of CS terminations in cats. We continuously infused muscimol unilaterally into sensorimotor cortex to silence neurons during the postnatal CS refinement period (weeks 3–7). Using anterograde transport of WGA-HRP, we examined the laterality of terminations from the muscimol-infused (i.e., silenced) and active sides in the spinal cord, as well as in the cuneate nucleus and red nucleus. We found that CS terminations from the muscimol-infused cortex were very sparse and limited to the contralateral side, while those from the active cortex maintained an immature bilateral topography. Controls (saline infusion, noninfusion) had dense, predominantly contralateral, CS terminations. There was a substantial decrease in the spinal gray matter area occupied by terminations from the side receiving the blockade and a concomitant increase in the area occupied by ipsilateral terminations from the active cortex. Optical density measurements of HRP reaction product from the active cortex in muscimol-infused animals showed substantial increases over controls in the ratio of ipsilateral to contralateral CS terminations for all laminae examined (IV–V, VI, VII). Our findings suggest that ipsilateral dorsal horn terminations reflect new axon growth during the refinement period because they are not present there earlier in development. Those in the ventral horn are present earlier in development and thus could reflect maintenance of transient terminations. Increased ipsilateral terminations from active cortex were due to recrossing of CS axons in lamina X and not to an increase in labeled CS axons in the ipsilateral white matter. Examination of brain stem terminations suggested that, between postnatal weeks 3 and 7, development of corticocuneate terminations also is activity-dependent but that development of corticorubral terminations is not. Activity-dependent CS development is a plausible mechanism by which early motor experiences could shape the anatomical and functional organization of the motor systems during a critical postnatal period. Received: 4 August 1998 / Accepted: 2 September 1998     

Effects of intrathecal clonidine injection on spinal reflexes and human locomotion in incomplete paraplegic subjects

We studied the effect of the intrathecal (i.t.) injection of clonidine (30, 60 and 90 μg) on the polysynaptic spinal reflexes (PSR) elicited by electrical stimulation of flexor reflex afferents (FRA), monosynaptic reflex and gait of 11 subjects with spinal cord injuries. The effect of clonidine administration on gait velocity, stride amplitude and duration was measured in eight subjects who were able to walk. Five subjects were able to walk after intrathecal injection of clonidine and three were not able to stand up. Three subjects improved their gait velocity after clonidine administration; one (S6) increased his stride amplitude; the two others decreased their cycle durations. The tibialis anterior seemed to be more regularly activated during gait. Spasticity was reduced dramatically (P<0.0001) after i.t. clonidine injection, but there was no statistically significant difference in the soleus H reflex (no effect on Hmax/Mmax). Clonidine administration decreased the amplitude of the early PSR (90–120 ms, N=4) and the threshold and maximal integrated EMG corresponding to the late response (140–450 ms, N=7). This effect was dose dependent (30, 60 and 90 μg). Placebo injection (N=4) caused no change. The changes in spinal reflexes, with a large reduction in spasticity, no change in motoneurone excitability and a large decrease in PSR, suggest that clonidine acts at a premotoneuronal level, possibly by presynaptic inhibition of group II fibres. The increase in gait velocity in three subjects could have been due to reduced spasticity or activation of spinal circuitry. Received: 30 June 1998 / Accepted: 1 June 1999     

Neurophysiological examination of the corticospinal system and voluntary motor control in motor-incomplete human spinal cord injury

This study employed neurophysiological methods to relate the condition of the corticospinal system with the voluntary control of lower-limb muscles in persons with motor-incomplete spinal cord injury. It consisted of two phases. In a group of ten healthy subjects, single and paired transcranial magnetic stimulation (TMS) of the motor cortex was used to study the behavior of the resulting motor evoked potentials (MEP) in lower-limb muscles. Interstimulus intervals (ISIs) of 15–100 ms were examined for augmentation of test MEPs by threshold or subthreshold conditioning stimuli. The second phase of this study examined eight incomplete spinal cord injured (iSCI) subjects, American Spinal Injury Association Impairment Scale C (n =5) and D (n =3) in whom voluntary motor control was quantified using the surface EMG (sEMG) based Voluntary Response Index (VRI). The VRI is calculated to characterize relative output patterns across ten lower-limb muscles recorded during a standard protocol of elementary voluntary motor tasks. VRI components were calculated by comparing the distribution of sEMG in iSCI subjects with prototype patterns collected from 15 healthy subjects using the same rigidly administered protocol, The resulting similarity index (SI) and magnitude values provided the measure of voluntary motor control. Corticospinal system connections were characterized by the thresholds for MEPs in key muscles. Key muscles were those that function as the prime-movers, or agonists for the voluntary movements from which the VRI data were calculated. Results include healthy-subject data that showed significant increases in conditioned MEP responses with paired stimuli of 15–50 ms ISI. Stimulus pairs of 75 and 100 ms showed no increase in MEP peak amplitude over that of the single-pulse conditioning stimulus alone, usually no response. For the iSCI subjects, 42% of the agonists responded to single-pulse TMS and 25% required paired-pulse TMS to produce an MEP. American Spinal Injury Association Impairment Scale component motor scores for agonist muscles, Quadriceps, Tibialis Anterior, and Triceps Surae, were significantly lower where MEPs could not be obtained (p <0.05). VRI values were also significantly lower for motor tasks with agonists that had no resting MEP (p <0.01). Therefore, the presence of a demonstrable connection between the motor cortex and spinal motor neurons in persons with SCI was related to the quality of post-injury voluntary motor control as assessed by the VRI.     

Asymmetric bipedal locomotion – an adaptive response to incomplete spinal injury in the chick

The purpose of this study was to compare the asymmetric gait induced by unilateral spinal cord injury in chicks with asymmetric gaits of other bipeds and quadrupeds. After lateral hemisection of the left thoracic spinal cord, kinetic (ground reaction forces) and kinematic (distance and timing) data were recorded as chicks moved overground unrestrained. Ground reaction forces were analyzed to obtain the mechanical energy changes throughout the stride. Kinematic measurements were obtained over a range of speeds to determine the velocity-dependent characteristics of the gait. Hemisected chicks adopted an asymmetric hopping gait in which the animals hopped from the right leg (contralateral to the lesion) onto the left (ipsilateral) leg but then fell forward onto the right leg. Mechanical energy fluctuations throughout a single stride (i.e., two steps) approximated the oscillations that occur during a single walking step of control animals. When examined over a range of velocities, asymmetries in limb timing remained constant, but distance measurements such as step length became more symmetric as speed increased.The results show that, after spinal hemisection, adaptations of the remaining neural circuitry permitted the production of a locomotor pattern that, in addition to providing effective support and propulsion, incorporated some of the energy-conserving mechanisms of the normal walk. Adjustment of this novel locomotor pattern for different velocities further demonstrates the flexibility of locomotor circuitry. Comparisons with other studies shows that this gait shares some temporal and energetic features with asymmetric gaits of several bipedal species, including humans. In particular, hemisected chicks and some hemiplegic humans adopt an asymmetric gait in which maximum energy recovery occurs during the stance of the affected limb; these similarities probably relate to common mechanical constraints imposed on bipedal forms of terrestrial locomotion. Received: 18 November 1997 / Accepted: 30 April 1998     

Long-term spinal cord injury increases susceptibility to isometric contraction-induced muscle injury

Complete spinal cord injury (SCI) results in inactivation and unloading of affected skeletal muscles. Unloading causes an increased susceptibility of muscle to contraction-induced injury. This study used magnetic resonance imaging (MRI) to test the hypothesis that isometric contractions would evoke greater muscle damage to the quadriceps femoris muscle (mQF) of SCI subjects than that of able-bodied (AB) controls. MR images were taken of the mQF prior to, immediately post, and 3 days post electromyostimulation (EMS). EMS consisted of five sets of ten isometric contractions (2 s on/6 s off, 1 min between sets) followed by another three sets of ten isometric contractions (1 s on/1 s off, 30 s between sets). Average muscle cross-sectional area (CSA) and the relative areas of stimulated and injured muscle were obtained from MR images by quantifying the number of pixels with an elevated T2 signal. SCI subjects had significantly greater relative area [90 (2)% versus 66 (4)%, P<0.05; mean (SE)] but a lesser absolute area [16 (3) cm² versus 44 (6) cm², P<0.05] of mQF stimulated than AB controls. During EMS, peak torque was reduced by 66% and 37% for SCI and control subjects, respectively. Three days post EMS, there was a greater relative area of stimulated mQF injured for the SCI subjects [25 (6)% versus 2 (1)%, P<0.05]. Peak torque remained decreased by 22% on day 3 in the SCI group only. These results indicate that affected muscle years after SCI is more susceptible to contraction-induced muscle damage, as determined by MRI, compared to AB controls. They also support the contention that electrically elicited isometric contractions are sufficient to cause muscle damage after a prolonged period of inactivity.     

Implanted spike wave electric stimulation promotes survival of the bone marrow mesenchymal stem cells and functional recovery in the spinal cord injured rats

Transplantation of bone marrow-derived mesenchymal stromal cells (BMSCs) into the injured spinal cord may provide therapeutic benefit, but its application is limited by their poor survival and low differentiation rate into neurons. Electrical stimulation (ES) has been reported to promote survival and differentiation of the BMSCs. Therefore we investigated whether implanted spike wave ES could improve survival of BMSCs after transplantation and result in functional improvement in animals with spinal cord injury. Our results showed that the number and ratio of survived BMSCs near the lesion site were significantly increased in the BMSCs+ES-treated group as compared to BMSCs transplantation or ES treatment alone group. Furthermore, results from BBB scales, SSEP and DTI demonstrated a significant improved functional recovery in the BMSCs+ES group. This indicated that implanted spike wave ES could promote the bioactivity of BMSCs and their survival. This represents a new therapeutic potential of the combination of BMSCs transplantation with implanted spike wave ES to treat spinal cord injury.     

Limitations in transplantation of astroglia-biomatrix bridges to stimulate corticospinal axon regrowth across large spinal lesion gaps

Regrowth of injured axons across rather small spinal cord lesion gaps and subsequent functional recovery has been obtained after many interventions. Long-distance regeneration of injured axons across clinically relevant large spinal lesion gaps is relatively unexplored. Here, we aimed at stimulating long-distance regrowth of the injured corticospinal (CS) tract. During development, an oriented framework of immature astrocytes is important for correct CS axon outgrowth. Furthermore, a continuous growth promoting substrate may be needed to maintain a CS axon regrowth response across relatively large spinal lesion gaps. Hence, we acutely transplanted poly(d,l)-lactide matrices, which after seeded with immature astrocytes render aligned astrocyte-biomatrix complexes (R. Deumens, et al. Alignment of glial cells stimulates directional neurite growth of CNS neurons in vitro. Neuroscience 125 (3) (2004) 591–604), into 2-mm long dorsal hemisection lesion gaps. In order to create a growth promoting continuum, astrocyte suspensions were also injected rostral and caudal to the lesion gap. During 2 months, locomotion was continuously monitored. Histological analysis showed that astrocytes injected into host spinal tissue survived, but did not migrate. None of the astrocytes on the biomatrices survived within the lesion gap. BDA-labeled CS axons did not penetrate the graft. However, directly rostral to the lesion gap, 120.9 ± 38.5% of the BDA-labeled CS axons were present in contrast to 12.8 ± 3.9% in untreated control animals. The observed anatomical changes were not accompanied by locomotor improvements as analyzed with the BBB and CatWalk. We conclude that although multifactorial strategies may be needed to stimulate long-distance CS axon regrowth, future studies should focus on enhancing the viability of cell/biomatrix complexes within large spinal lesion gaps.     

Ankle dexterity remains intact in patients with incomplete spinal cord injury in contrast to stroke patients

The present study assessed the influence of visual feedback on stance stability and soleus H-reflex excitability. The centre of pressure (COP) displacement was measured in upright stance on a rigid surface (stable surface) and on a spinning top (unstable surface) while subjects either received “normal” visual feedback (without laser pointer = WLP) or pointed with a laser pointer on a target on the wall (LP). In order to verify that laser pointing influenced visual feedback, two additional experiments were conducted: (1) Subjects performed a finger reaction task which was thought to increase attention and cognitive demands without alteration of the visual feedback. (2) The effect of laser pointing on the wall was compared with pointing at a board, which was attached to the subjects themselves. In this case, the laser point could not serve as a reference for sway because the board moved in synchrony with the body. On stable and unstable surface, COP displacement was reduced in the LP compared to the WLP task (−17 cm ± 6, P < 0.05; −14 cm ± 6, P < 0.05). Conversely, H-reflexes were greater in the LP condition (stable: +20 μV ± 30, not significant; unstable +115 μV ± 40, P < 0.05). Stance stability and H-reflex modulation were negatively correlated (R ² = −0.5; P < 0.001). The finger reaction task did neither influence COP displacement nor H-reflexes. Pointing at the body-fixed target did not alter COP displacement. These findings suggest that postural sway can be reduced by a handheld laser pointer targeting on an external reference point. It is argued that altered visual input was responsible for modulating the H-reflex.     

Level of spinal cord lesion determines locomotor activity in spinal man

Recent studies have demonstrated that coordinated stepping movements can be induced in patients with complete para-/tetraplegia, when they were standing on a moving treadmill with their body weight partially unloaded and external assistance. The aim of this study was to determine which part of the spinal cord generated the locomotor pattern. In patients with complete paraplegia due to lesions at different levels of the spinal cord, the locomotor pattern was compared with that of healthy subjects. Any similarities in electromyographic (EMG) activity of gastrocnemius and tibialis anterior muscles between the patients and healthy subjects were reflected by the analysis of the variation ratio and amplitudes of the EMG activity. It was found that the higher the level of spinal cord lesion the more ”normal” was the locomotor pattern. This suggests that neuronal circuits underlying locomotor ”pattern generation” in man are not restricted to any specific level(s) of the spinal cord, but that an intricate neuronal network contributing to bipedal locomotion extends from thoracolumbal to cervical levels. Received: 16 October 1998 / Accepted: 21 April 1999     

Soleus H-reflex modulation during body weight support treadmill walking in spinal cord intact and injured subjects

The soleus H-reflex modulation pattern was investigated in ten spinal cord intact subjects during treadmill walking at varying levels of body weight support (BWS), and nine spinal cord injured (SCI) subjects at a BWS level that promoted the best stepping pattern. The soleus H-reflex was elicited by tibial nerve stimulation with a single 1-ms pulse at an intensity that the M-waves ranged from 4 to 8% of the maximal M-wave (M_max). During treadmill walking, the H-reflex was elicited every four steps, and stimuli were randomly dispersed across the gait cycle which was divided into 16 equal bins. EMGs were recorded with surface electrodes from major left and right hip, knee, and ankle muscles. M-waves and H-reflexes at each bin were normalized to the M_max elicited at 60–100 ms after the test reflex stimulus. For every subject, the integrated EMG area of each muscle was established and plotted as a function of the step cycle phase. The H-reflex gain was determined as the slope of the relationship between H-reflex and soleus EMG amplitudes at 60 ms before H-reflex elicitation for each bin. In spinal cord intact subjects, the phase-dependent H-reflex modulation, reflex gain, and EMG modulation pattern were constant across all BWS (0, 25, and 50) levels, while tibialis anterior muscle activity increased with less body loading. In three out of nine SCI subjects, a phase-dependent H-reflex modulation pattern was evident during treadmill walking at BWS that ranged from 35 to 60%. In the remaining SCI subjects, the most striking difference was an absent H-reflex depression during the swing phase. The reflex gain was similar for both subject groups, but the y-intercept was increased in SCI subjects. We conclude that the mechanisms underlying cyclic H-reflex modulation during walking are preserved in some individuals after SCI.     

Enhanced excitability of the corticospinal pathway of the ankle extensor and flexor muscles during standing in humans

The purpose of this study was to investigate how the recruitment properties of the corticospinal pathway are modulated in the soleus (SOL) and tibialis anterior (TA) muscles depending on postures. A wide range of stimulus intensities were applied via transcranial magnetic stimulation over the primary motor cortex during standing (STD) and sitting (SIT) with a comparable background activity level in each muscle. The relationship between the stimulation intensities and the size of motor-evoked potentials was assessed by the Boltzmann sigmoid function, which is characterized by a plateau value, maximum slope, and threshold. The plateau value and maximum slope were significantly higher during STD than during SIT in the SOL muscle (STD vs. SIT, plateau value: 50.0 ± 21.8 vs. 33.9 ± 12.3 mV ms, maximal slope: 1.6 ± 0.7 vs. 1.2 ± 0.5 mV ms/% maximal stimulator output). Similar changes of the parameters were also observed in the TA muscle (STD vs. SIT, plateau value: 71.0 ± 22.9 vs. 41.4 ± 16.1 mV ms, maximal slope: 5.0 ± 2.0 vs. 2.5 ± 0.7 mV ms/% maximal stimulator output). The threshold did not differ significantly between the two conditions and both muscles. These results indicate that the central nervous system requires a different control for each postural condition; that is, the relative balance of the excitatory and inhibitory inputs to the corticospinal pathways as well as the number of neurons of subliminal fringe in the corticospinal pathway was increased during STD compared with those during SIT.     

Embryonic stem cells inhibit expression of erythropoietin in the injured spinal cord

Recent observations have demonstrated neuroprotective role of erythropoietin (Epo) and Epo receptor in the central nervous system. Here we examined Epo function in the murine spinal cord after transplantation of pluripotent mouse embryonic stem (ES) cells pre-differentiated towards neuronal type following spinal cord injury. Expression of Epo was measured at both mRNA and protein levels in the ES cells as well as in the spinal cords after 1 and 7 days. Our data demonstrated that expression of Epo mRNA, as well as its protein content, in ES cells was significantly decreased after differentiation procedure. In the spinal cords, analysis showed that Epo mRNA level was significantly decreased after 1 day of ES cell injections in comparison to media-injected control. Epo protein level detected by Western blot was diminished as well. Examination of Epo production in the injured spinal cords after media or ES cells injections by indirect immunofluorescence showed increased Epo-immunopositive staining after media injections 1 day after injection. In contrast, ES cell transplantation did not induce Epo expression. Seven days after ES cell injections, Epo-immunopositive cells’ distribution in the ipsilateral side was not changed, while the intensity of immunostaining on the contralateral side was increased, approaching levels in control media-injected tissues. Our data let us to presume that previously described immediate positive effects of ES cells injected into the injured zone of spinal cord are not based on Epo, but on other factors or hormones, which should be elucidated further.     

A mechanical microconnector system for restoration of tissue continuity and long-term drug application into the injured spinal cord

Complete transection of the spinal cord leaves a gap of several mm which fills with fibrous scar tissue. Several approaches in rodent models have used tubes, foams, matrices or tissue implants to bridge this gap. Here, we describe a mechanical microconnector system (mMS) to re-adjust the retracted spinal cord stumps. The mMS is a multi-channel system of polymethylmethacrylate (PMMA), designed to fit into the spinal cord tissue gap after transection, with an outlet tubing system to apply negative pressure to the mMS thus sucking the spinal cord stumps into the honeycomb-structured holes. The stumps adhere to the microstructure of the mMS walls and remain in the mMS after removal of the vacuum. We show that the mMS preserves tissue integrity and allows axonal regrowth at 2, 5 and 19 weeks post lesion with no adverse tissue effects like in-bleeding or cyst formation. Preliminary assessment of locomotor function in the open field suggested beneficial effects of the mMS. Additional inner micro-channels enable local substance delivery into the lesion center via an attached osmotic minipump. We suggest that the mMS is a suitable device to adapt and stabilize the injured spinal cord after surgical resection of scar tissue (e.g., for chronic patients) or traumatic injuries with large tissue and bone damages.     

Facilitation of spinal sciatic neuron responses to hindpaw thermal stimulation after formalin injection in rat tail

 A recent model of formalin injection in the tail induced a facilitation of the hindpaw withdrawal reflexes. In the present work we tried, after injecting formalin into the tail of the albino rat, to determine the spontaneous activity and response changes of lumbar sciatic wide-dynamic-range neurons to thermal stimulations of the paw at 45°C and 48°C (the respective thresholds for noxious and non-noxious thermal stimuli). The experiments were carried out with multiple recording electrodes placed in a comb array in the lumbar segments of the spinal cord at L4–L6 level in the sciatic projection field. A significant facilitation of the spontaneous activity was already evident 2 min after injection; at 5 min there were strong facilitations to the thermal stimuli. Stimuli at 45°C, often ineffective prior to the formalin injection, became strongly excitatory. Stimuli at 48°C evoked more conspicuous responses. This facilitatory effect on spontaneous and thermal responses followed a time-course comparable to that described for the excitations seen after paw formalin injection, but the duration was more prolonged, lasting more than 2 h. These data indicate a facilitatory role of the formalin effects on spinal sciatic neurons after injection in the tail. It is proposed that the mutual effects of spinal neurons in distant spinal segments could explain the facilitation and such a time-course, and that a role in the development of prolonged pain could be envisaged. Received: 24 June 1998 / Accepted: 18 January 1999