Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

Decoding cerebro-spinal signatures of human behavior: Application to motor sequence learning.

Mapping the neural patterns that drive human behavior is a key challenge in neuroscience. Even the simplest of our everyday actions stem from the dynamic and complex interplay of multiple neural structures across the central nervous system (CNS). Yet, most neuroimaging research has focused on investigating cerebral mechanisms, while the way the spinal cord accompanies the brain in shaping human behavior has been largely overlooked. Although the recent advent of functional magnetic resonance imaging (fMRI) sequences that can simultaneously target the brain and spinal cord has opened up new avenues for studying these mechanisms at multiple levels of the CNS, research to date has been limited to inferential univariate techniques that cannot fully unveil the intricacies of the underlying neural states. To address this, we propose to go beyond traditional analyses and instead use a data-driven multivariate approach leveraging the dynamic content of cerebro-spinal signals using innovation-driven coactivation patterns (iCAPs). We demonstrate the relevance of this approach in a simultaneous brain-spinal cord fMRI dataset acquired during motor sequence learning (MSL), to highlight how large-scale CNS plasticity underpins rapid improvements in early skill acquisition and slower consolidation after extended practice. Specifically, we uncovered cortical, subcortical and spinal functional networks, which were used to decode the different stages of learning with a high accuracy and, thus, delineate meaningful cerebro-spinal signatures of learning progression. Our results provide compelling evidence that the dynamics of neural signals, paired with a data-driven approach, can be used to disentangle the modular organization of the CNS. While we outline the potential of this framework to probe the neural correlates of motor learning, its versatility makes it broadly applicable to explore the functioning of cerebro-spinal networks in other experimental or pathological conditions.

Comparison of spinal magnetic resonance imaging and classical clinical factors in predicting motor capacity in amyotrophic lateral sclerosis.

BACKGROUND: Motor capacity is crucial in amyotrophic lateral sclerosis (ALS) clinical trial design and patient care. However, few studies have explored the potential of multimodal MRI to predict motor capacity in ALS. This study aims to evaluate the predictive value of cervical spinal cord MRI parameters for motor capacity in ALS compared to clinical prognostic factors. METHODS: Spinal multimodal MRI was performed shortly after diagnosis in 41 ALS patients and 12 healthy participants as part of a prospective multicenter cohort study, the PULSE study (NCT00002013-A00969-36). Motor capacity was assessed using ALSFRS-R scores. Multiple stepwise linear regression models were constructed to predict motor capacity at 3 and 6 months from diagnosis, based on clinical variables, structural MRI measurements, including spinal cord cross-sectional area (CSA), anterior-posterior, and left-to-right cross-section diameters at vertebral levels from C1 to T4, and diffusion parameters in the lateral corticospinal tracts (LCSTs) and dorsal columns. RESULTS: Structural MRI measurements were significantly correlated with the ALSFRS-R score and its sub-scores. And as early as 3 months from diagnosis, structural MRI measurements fit the best multiple linear regression model to predict the total ALSFRS-R (R2 = 0.70, p value = 0.0001) and arm sub-score (R2 = 0.69, p value = 0.0002), and combined with DTI metric in the LCST and clinical factors fit the best multiple linear regression model to predict leg sub-score (R2 = 0.73, p value = 0.0002). CONCLUSIONS: Spinal multimodal MRI could be promising as a tool to enhance prognostic accuracy and serve as a motor function proxy in ALS.

Spinal cord multi-parametric magnetic resonance imaging for survival prediction in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Assessing survival is a critical issue in patients with amyotrophic lateral sclerosis (ALS). Neuroimaging seems to be promising in the assessment of disease severity and several studies also suggest a strong relationship between spinal cord (SC) atrophy described by magnetic resonance imaging (MRI) and disease progression. The aim of the study was to determine the predictive added value of multimodal SC MRI on survival. METHODS: Forty-nine ALS patients were recruited and clinical data were collected. Patients were scored on the Revised ALS Functional Rating Scale and manual muscle testing. They were followed longitudinally to assess survival. The cervical SC was imaged using the 3 T MRI system. Cord volume and cross-sectional area (CSA) at each vertebral level were computed. Diffusion tensor imaging metrics were measured. Imaging metrics and clinical variables were used as inputs for a multivariate Cox regression survival model. RESULTS: On building a multivariate Cox regression model with clinical and MRI parameters, fractional anisotropy, magnetization transfer ratio and CSA at C2-C3, C4-C5, C5-C6 and C6-C7 vertebral levels were significant. Moreover, the hazard ratio calculated for CSA at the C3-C4 and C5-C6 levels indicated an increased risk for patients with SC atrophy (respectively 0.66 and 0.68). In our cohort, MRI parameters seem to be more predictive than clinical variables, which had a hazard ratio very close to 1. CONCLUSIONS: It is suggested that multimodal SC MRI could be a useful tool in survival prediction especially if used at the beginning of the disease and when combined with clinical variables. To validate it as a biomarker, confirmation of the results in bigger independent cohorts of patients is warranted.

Repetitive transcranial magnetic stimulation and transcranial direct current stimulation in motor rehabilitation after stroke: an update.

Stroke is a leading cause of adult motor disability. The number of stroke survivors is increasing in industrialized countries, and despite available treatments used in rehabilitation, the recovery of motor functions after stroke is often incomplete. Studies in the 1980s showed that non-invasive brain stimulation (mainly repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]) could modulate cortical excitability and induce plasticity in healthy humans. These findings have opened the way to the therapeutic use of the 2 techniques for stroke. The mechanisms underlying the cortical effect of rTMS and tDCS differ. This paper summarizes data obtained in healthy subjects and gives a general review of the use of rTMS and tDCS in stroke patients with altered motor functions. From 1988 to 2012, approximately 1400 publications were devoted to the study of non-invasive brain stimulation in humans. However, for stroke patients with limb motor deficit, only 141 publications have been devoted to the effects of rTMS and 132 to those of tDCS. The Cochrane review devoted to the effects of rTMS found 19 randomized controlled trials involving 588 patients, and that devoted to tDCS found 18 randomized controlled trials involving 450 patients. Without doubt, rTMS and tDCS contribute to physiological and pathophysiological studies in motor control. However, despite the increasing number of studies devoted to the possible therapeutic use of non-invasive brain stimulation to improve motor recovery after stroke, further studies will be necessary to specify their use in rehabilitation.

Both L-DOPA and HFS-STN restore the enhanced group II spinal reflex excitation to a normal level in patients with Parkinson's disease.

OBJECTIVE: To investigate the contribution of group II spinal pathways in Parkinsonian upper limb rigidity and the modulation of spinal excitability of group I and group II pathways by L-DOPA and subthalamic nucleus-high-frequency stimulation (STN-HFS). METHODS: The effect of ulnar nerve electrical stimulation on Flexor Carpi Radialis Electromyogram (FCR EMG) was investigated in two groups of patients: patients receiving medication (MED group) and chronically surgically implanted patients (DBS group). Results were compared in patients ON and OFF treatment, and between patients and control subjects. RESULTS: The resulting long-lasting facilitation in FCR EMG had similar characteristics in all groups, and surface area was assessed in analysis windows corresponding to the parts supposed to be mediated by non-monosynaptic spinal pathways to FCR motoneurones, fed by hand muscle group I and group II afferents (Lourenço et al., 2006). In both the MED and DBS groups, the group I excitation was not altered but the group II excitation was particularly enhanced when OFF treatment, compared to controls, and both L-DOPA and STN-HFS restored the group II spinal excitation to normal level. CONCLUSION: Both L-DOPA and STN-HFS influence the metabolism of monoamines in the midbrain, and restore the descending neuromodulation on group II spinal reflex. SIGNIFICANCE: These results further support a group II contribution to the enhanced long latency response (LLR) to muscle stretch observed in wrist muscles of rigid Parkinson's disease (PD) patients.

Enhanced spinal excitation from ankle flexors to knee extensors during walking in stroke patients.

OBJECTIVES: It is still unclear to what an extent altered reflex activity contributes to gait deficit following stroke. Spinal group I and group II excitations from ankle dorsiflexors to knee extensors were investigated during post-stroke walking. METHODS: Electrical stimulation was applied to the common peroneal nerve (CPN) in the early stance, and the short-latency biphasic excitation in Quadriceps motoneurones was evaluated from the Vastus Lateralis (VL) rectified and averaged (N=50) EMG activity in 14 stroke patients walking at 0.6-1.6 km/h, and 14 control subjects walking at 3.2-4.8 and at 1 km/h. RESULTS: The second peak of the CPN-induced biphasic facilitation in VL EMG activity, which is likely mediated by group II excitatory pathways, was larger on the paretic side of the patients, as compared to their nonparetic side or control subjects, whatever their walking speed. CONCLUSIONS: The spinal, presumed group II, excitation from ankle dorsiflexors to knee extensors is particularly enhanced during post-stroke walking probably due to plastic adaptations in the descending control. SIGNIFICANCE: This adaptation may help to stabilize the knee in early stance when the patients have recover ankle dorsiflexor functions.

The estimation of short intra-cortical inhibition depends on the proportion of spinal motoneurones activated by corticospinal inputs.

OBJECTIVE: The high variability of SICI limits its utility and by extension that of TMS in clinical neurophysiology. Non-linear summation of descending volleys due to heterogeneous motoneurone properties, on which MEP size depends, has not previously been implicated as an issue in SICI evaluation. METHODS: MEP size and SICI were normalised to the test MEP (mV), and as a percentage of M(max) to take account of the proportion of motoneurone pool activated by TMS. Two EMG systems, producing large and small MEPs, were used to determine how the normalisation affected MEPs of different amplitude. RESULTS: M(max) normalisation (i) counteracted the influence of recording conditions on the MEP size, (ii) revealed a significant influence of the test size on SICI (between medium and large MEPs), and of test size on the conditioning intensity (the larger the MEP, the stronger the SICI), and (iii) decreased the variability. CONCLUSIONS: Data normalised to M(max) better reflect the motoneurone recruitment after SICI. To enhance reproducibility, MEP should be normalised to M(max). This adjusts for some of the non-linear properties at the spinal, and possibly, at cortical levels. SIGNIFICANCE: To reduce variability is important because TMS is becoming widely adopted and is being used in patients.

Reduction of common motoneuronal drive on the affected side during walking in hemiplegic stroke patients.

OBJECTIVE: The objective of this study was to use motor unit coupling in the time and frequency domains to obtain evidence of changes in motoneuronal drive during walking in subjects with stroke. METHODS: Paired tibialis anterior (TA) EMG activity was sampled during the swing phase of treadmill walking in eight subjects with unilateral stroke. RESULTS: On the unaffected side, short-term synchronization was evident from the presence of a narrow central peak in cumulant densities and from the presence of significant coherence between these signals in the 10-25 Hz band. Such indicators of short-term synchrony were either absent or very small on the affected side. Instead, pronounced 10 Hz coupling was observed. CONCLUSIONS: It is suggested that reduced corticospinal drive to the spinal motoneurones is responsible for the reduced short-term synchrony and coherence in the 10-25 Hz frequency band on the affected side in hemiplegic patients during walking. SIGNIFICANCE: This is of importance for understanding the mechanisms responsible for reduced gait ability and development of new strategies for gait restoration.

Abnormal spinal interactions from hand afferents to forearm muscles in writer's cramp.

OBJECTIVE: Spinal reflexes from hand to wrist muscles were investigated in writer's cramp. METHODS: Stimulus-triggered rectified EMG averages after ulnar nerve and cutaneous stimulation, in wrist flexors and extensors during tonic contraction, were compared in 18 controls and 19 patients. RESULTS: On the patient dystonic side, ulnar-induced EMG suppression was decreased in wrist extensors, and facilitation in wrist flexors modified dependent on the dystonic wrist posture during writing. No change was found on the patient non-dystonic side. Cutaneous stimulation increased wrist flexor EMG on both sides of the patients with normal wrist posture during writing, but had no effect in controls and patients with abnormal wrist posture. CONCLUSIONS: Comparison between cutaneous and mixed nerve stimuli suggests that spindle afferents from intrinsic hand muscles may mediate patients' ulnar-induced EMG modulations. Abnormal proprioceptive control was only observed on dystonic side, while bilateral unusual cutaneous control was found in patients. Changes in spinal transmission were partly related to the dystonic wrist posture, suggesting that systems involved in sensory processing can be differentially altered in writer's cramp. SIGNIFICANCE: Changes in spinal transmission, probably related to peripheral and/or cortical inputs, might either take part in primary or adaptive mechanisms underlying writer's cramp.

Effects produced in human arm and forearm motoneurones after electrical stimulation of ulnar and median nerves at wrist level.

Effects of electrical stimulation of ulnar and median nerves at wrist level were investigated in post-stimulus time histograms (PSTHs) of single motor units from both flexors and extensors in human arm and forearm. Stimulation of ulnar nerve produced late (mean extra time-after monosynaptic group Ia excitation-10.7 +/- 0.1 ms) high-threshold (>1.2 x motor threshold, MT) excitation, which was not reproduced by purely cutaneous stimulation, in all the investigated motor nuclei except in Extensor Carpi Radialis. Stimulation of median nerve, and of the skin of fingers II and III (at palmar side level), produced short latency inhibition (mean extra time 3.8 +/- 0.3 ms), which was most often truncated or followed by late excitation (mean extra time 11.8 +/- 0.3 ms); both effects were of low threshold (0.8 x MT). Short latency inhibition was very strong, and late excitation was rare and weak in almost all the investigated motor units except in those supplying flexors in forearm, in which the main effect was the late facilitation (stronger than in other motoneurones). Since extra time was not more than 13 ms, it is suggested that the late effects may be mediated through spinal pathways, at least during their 3-5 first ms. Based on the electrophysiological results and on the anatomical characteristics of ulnar and median nerves, it is assumed that ulnar-induced late high-threshold peak in PSTHs might reflect group II excitation in spinal motoneurones, and median-induced modifications in motor unit discharge, mainly cutaneous control of motoneurone discharge. Since the central delay of median-induced inhibition is longer the more caudal the motoneurone, inhibitory propriospinal-like interneurones are supposed to mediate cutaneous inhibitory control from hand upon muscles in arm and forearm. Potential roles of proprioceptive and cutaneous control from hand to more proximal musculature, provided by ulnar and median nerve, respectively, during precise hand movements are discussed.

Group II excitations from plantar foot muscles to human leg and thigh motoneurones.

Projections of group II afferents from intrinsic foot muscles to lower limb motoneurones were investigated in humans after electrical stimuli were applied to the tibial nerve (TN) at ankle level, using modulation of the quadriceps H reflex, on-going EMG of the quadriceps and peroneus brevis, and PSTHs of single quadriceps, biceps, semitendinosus, tibialis anterior, and peroneus brevis motor units. TN stimulation evoked late and high-threshold excitation in all leg and thigh muscles investigated. The mean latency of the late excitation was 13.5+/-0.4 ms longer than that of the heteronymous monosynaptic Ia excitation, and the more caudal the motor nucleus the longer the central delay of the late effect, suggesting mediation through interneurones located rostral to motoneurones. The electrical threshold and conduction velocity of the largest diameter fibres evoking the late excitation were estimated to be approximately 2 and 0.67 times, respectively, those of the fastest Ia afferents, i.e. consistent with a mediation by group II afferents. Stimulation of the skin areas innervated by TN did not evoke late excitations. Further support for mediation through group II afferents was provided by the findings that: 1. the latency of the TN-induced late and high-threshold excitation in Per brev units was more delayed by cooling the nerve than that of the excitation evoked by group I afferents, and 2. tizanidine intake (known to depress selectively transmission of group II effects) suppressed the TN-induced late and high-threshold excitation whereas the group I facilitation was not modified.

Perception of non-voluntary brief contractions in normal subjects and in a deafferented patient.

The accuracy of force perception by human subjects in the absence of voluntary motor command was evaluated by exploring how they perceived isometric twitches of wrist extensor muscles produced by external stimulation. Twelve normal subjects and a well-known patient lacking large-diameter afferent fibres (GL) performed estimation, production and reproduction tasks. Magnetic stimulation of the radial nerve and, in normal subjects, transcranial magnetic stimulation (TMS) of the motor cortex were used to produce weak brief non-voluntary twitches. In estimation tasks, the subjects had to ascribe verbal marks on a 1-5 scale to the forces of stimulation-induced twitches. Loose covariations of marks and forces were observed, while directions of force variations between successive twitches were relatively well detected. GL did less well than normal subjects in detecting directions of force variations. In production tasks, subjects had to produce twitches matching verbal command marks in a 1-5 range, with or without visual feedback. Performances of normal subjects and GL resembled those of estimation tasks and were not improved by visual feedback. In reproduction tasks, subjects had to duplicate stimulation-induced test twitches: first without visual feedback, second with and third again without. Large errors were observed but all subjects did better with visual feedback. In the third step, improvement with respect to the first one was significantly more marked with TMS than with peripheral stimulation. GL improved her performance in the third step, possibly because she could use information provided by group III and group IV afferents still present in her nerves. Altogether, for normal subjects (1) the performances in estimation tasks are consistent with the known behaviour of Golgi tendon organs as observed in animal experiments, and (2) results observed in reproduction tasks suggest that cortical stimulation might elicit, in addition to corticospinal activation of motoneurones, collateral discharges that could be stored as a memory of motor command.

Modulation of heteronymous reflexes from ankle dorsiflexors to hamstring muscles during human walking.

In 16 human subjects, stimulation of the common peroneal nerve (CPN) was applied during walking and standing. The effect of the stimulation was evaluated from the rectified and averaged biceps femoris (BF) electromyographic (EMG) activity. In the swing phase of walking, the CPN stimulation evoked a suppression in the BF EMG in 12 of the subjects. In the early stance phase, the suppression was replaced by facilitation at a similar latency in 9 of the subjects. Of the other 3 subjects, in whom a suppression was observed during swing, a decrease in the suppression was observed in the stance phase in two of them. During a voluntary co-contraction of BF and tibialis anterior while standing, a suppression similar to that observed in the swing phase was observed. The thresholds of the suppression and facilitation were identical, suggesting that afferents of similar diameter were responsible. Cutaneous stimuli, which mimicked the sensation evoked by the CPN stimulation, but without activation of muscle afferents, did not produce similar effects in the BF EMG activity. It is suggested that the observed response and reflex reversal may reflect opening of an excitatory group I pathway in the early stance phase of walking with a concomitant shut-down of heteronymous group I inhibition.

Modulation of non-monosynaptic excitation from ankle dorsiflexor afferents to quadriceps motoneurones during human walking.

Modulation of non-monosynaptic excitation from ankle dorsiflexors to quadriceps (Q) motoneurones during human treadmill walking was investigated in 25 healthy human subjects. Stimulation of the common peroneal nerve (CPN) evoked a biphasic facilitation in the rectified and averaged (n = 50) Q electromyographic (EMG) activity between 0 and 100 ms after heel strike. Prior to heel strike, the stimulation had no effect on the Q EMG. The latency of both peaks in the response was too long to be explained by a monosynaptic pathway to Q motoneurones. During voluntary tonic co-contraction of Q and tibialis anterior (TA) while standing, only the first of the two peaks was evoked by the CPN stimulation despite a background EMG activity level in the Q and TA muscles corresponding to that observed 30-60 ms after heel strike during walking. Stimulation of cutaneous nerves did not evoke a similar biphasic facilitation in the Q motoneurones, which suggests that muscular afferents mediate the response. The second peak had a higher threshold than the earlier peak. During cooling of the CPN, the latency of the second peak was more prolonged than the latency of the earlier peak. This suggests that afferents of different diameters contributed to the two peaks. It is proposed that afferents from TA assist the contraction of Q during walking via spinal interneurones to stabilize the knee joint and maintain upright posture during walking.

Interruption of a relay of corticospinal excitation by a spinal lesion at C6-C7.

In a patient with a limited lesion of the spinal cord at the C6-C7 junction, ulnar and superficial radial-induced modulations of the motor evoked potentials (MEP) and of ongoing electromyographic (EMG) activity were observed in the biceps (above the lesion) but not in the triceps (below the lesion). This suggests an interruption of the axons of cervical propriospinal neurons. This relay transmits an indirect (disynaptic) component of corticospinal excitation to human upper limb motoneurons. Changes in it might be involved in compensatory mechanisms following central motor disorders.

Suppression of EMG activity by transcranial magnetic stimulation in human subjects during walking.

1. The involvement of the motor cortex during human walking was evaluated using transcranial magnetic stimulation (TMS) of the motor cortex at a variety of intensities. Recordings of EMG activity in tibialis anterior (TA) and soleus muscles during walking were rectified and averaged. 2. TMS of low intensity (below threshold for a motor-evoked potential, MEP) produced a suppression of ongoing EMG activity during walking. The average latency for this suppression was 40.0 +/- 1.0 ms. At slightly higher intensities of stimulation there was a facilitation of the EMG activity with an average latency of 29.5 +/- 1.0 ms. As the intensity of the stimulation was increased the facilitation increased in size and eventually a MEP was clear in individual sweeps. 3. In three subjects TMS was replaced by electrical stimulation over the motor cortex. Just below MEP threshold there was a clear facilitation at short latency (approximately 28 ms). As the intensity of the electrical stimulation was reduced the size of the facilitation decreased until it eventually disappeared. We did not observe a suppression of the EMG activity similar to that produced by TMS in any of the subjects. 4. The present study demonstrates that motoneuronal activity during walking can be suppressed by activation of intracortical inhibitory circuits. This illustrates for the first time that activity in the motor cortex is directly involved in the control of the muscles during human walking.

Group I projections from intrinsic foot muscles to motoneurones of leg and thigh muscles in humans.

1. Group I projections from intrinsic plantar muscles to motoneurones (MNs) of human leg and thigh muscles were investigated. Changes in firing probability of single motor units (MUs) in the tibialis anterior (TA), peroneus brevis (Per brev), soleus (Sol), gastrocnemius medialis (GM), vastus lateralis (VL), semitendinosus (ST) and biceps (Bi) were studied after electrical stimuli applied to: (i) the tibial nerve (TN) at ankle level, (ii) the corresponding homonymous nerve, and (iii) the skin of the heel, to mimic the TN-induced cutaneous sensation. 2. Homonymous facilitation, attributable to monosynaptic Ia excitation, was found in all the sampled units. Early heteronymous excitation elicited by TN stimulation was found in many MUs. Later effects (3-5 ms central delay) were bigger and more frequently observed: excitation in most TA and Per brev MUs, and inhibition in most Sol, GM and Bi MUs and in many ST and VL MUs. The low threshold (approximately 0.5-0.6 x motor threshold) and the inability of a pure cutaneous stimulation to reproduce these effects (except the late excitation in TA MUs) indicate that they were due to stimulation of group I muscle afferents. 3. The early excitation was accepted to be monosynaptic when its central delay differed from that of the homonymous Ia excitation by less than 0.5 ms. Such a significant TN-induced monosynaptic Ia excitation was found in MUs belonging to all leg and thigh motor nuclei tested. Although its mean strength was relatively weak, it is argued that these monosynaptic connections might affect already depolarized MNs. 4. The late excitation found in TA and Per brev MUs is argued to be mediated through interneurones located rostral to MNs. 5. The late suppression, found in most Sol, GM and Bi MUs, and in many ST and VL MUs, was the dominant effect. It was accompanied by an inhibition of the Sol and quadriceps H reflexes at rest, and therefore reflects an inhibition directed to MNs. Its long latency is argued to reflect transmission by interneurones located rostral to MNs (the inhibitory counterpart of non-monosynaptic excitation). 6. The functional implications of these connections are discussed with respect to the requirements of the stance phase of human walking and running.

Corticospinal excitation of presumed cervical propriospinal neurones and its reversal to inhibition in humans.

1. This study addresses whether in human subjects indirect corticospinal excitation of upper limb motoneurones (MNs) relayed through presumed cervical propriospinal neurones (PNs) is paralleled by corticospinal activation of inhibitory projections to these premotoneurones. 2. The responses to transcranial magnetic stimulation (TMS), whether assessed as the compound motor-evoked potential (MEP) or the peak of corticospinal excitation elicited in the post-stimulus time histograms (PSTHs) of single motor units, were conditioned by weak volleys to musculo-cutaneous, ulnar and superficial radial nerves. 3. Afferent volleys, which hardly modified the H reflex, significantly facilitated the corticospinal response produced by weak TMS. In PSTHs, the central delay of the peripheral facilitation of the peak of corticospinal excitation in MNs located at either end of the cervical enlargement was longer the more caudal the MN pool, suggesting an interaction in premotoneurones located rostral to the tested MNs. 4. Small increases in the strength of TMS (approximately 2--5 % of the maximal stimulator output) caused the facilitation to disappear and then to be reversed to inhibition. The facilitatory and inhibitory effects had the same latencies and spared the initial 0.5--1 ms of the corticospinal excitatory response. Both effects were more readily demonstrable when there was a co-contraction of the target muscle and the muscle innervated by nerve used for the conditioning stimulus. 5. The above features suggest that the inhibition resulted from disfacilitation due to suppression of corticospinal excitation passing through the presumed premotoneuronal relay. The reversal of the facilitation to inhibition by stronger corticospinal volleys is consistent with a well-developed system of 'feedback inhibitory interneurones' activated by corticospinal and afferent inputs inhibiting the presumed propriospinal excitatory premotoneurones. 6. It is argued that these findings might explain why simply stimulating the pyramidal tract or the motor cortex would fail to demonstrate this indirect corticospinal projection in the macaque monkey and in humans.

Distribution of non-monosynaptic excitation to early and late recruited units in human forearm muscles.

The distribution of monosynaptic and nonmonosynaptic excitation was investigated within flexor carpi radialis (FCR) and extensor carpi radialis (ECR) motoneurone (MN) pools. FCR H reflexes of different size were conditioned by various conditioning stimuli eliciting different effects: (1) musculocutaneous-induced non-monosynaptic excitation of FCR MNs at the onset of biceps contraction, (2) heteronymous monosynaptic Ia facilitation, (3) reciprocal Ia inhibition, and (4) presynaptic inhibition of Ia terminals. Musculocutaneous-induced non-monosynaptic excitation increased continuously with the size of the unconditioned reflex. In contrast, heteronymous monosynaptic Ia excitation first increased and then decreased, with increases in the unconditioned reflex size, reciprocal inhibition and presynaptic inhibition showing an approximately similar tendency. This suggests that the non-monosynaptic excitation is distributed more evenly to early and late recruited MNs than monosynaptic Ia excitation, reciprocal inhibition and presynaptic inhibition. A different pattern of homonymous radial-induced monosynaptic and non-monosynaptic excitation was also found for individual ECR MNs investigated with the poststimulus time histogram (PSTH) method. Whereas the monosynaptic Ia excitation tended to be most marked in lower threshold MUs, the nonmonosynaptic excitation was evenly distributed to lower and higher threshold MUs. We propose that the even distribution of the non-monosynaptic excitation in the motoneuronal pool may be of significance when it is necessary to activate a wide range of MNs more or less simultaneously.