Plastic changes in spinal synaptic transmission following botulinum toxin A in patients with post-stroke spasticity.

OBJECTIVE: The therapeutic effects of intramuscular injections of botulinum toxin-type A on spasticity can largely be explained by its blocking action at the neuromuscular junction. Botulinum toxin-type A is also thought to have a central action on the functional organization of the central nervous system. This study assessed the action of botulinum toxin-type A on spinal motor networks by investigating post-activation depression of the soleus H-reflex in post-stroke patients. Post-activation depression, a presynaptic mechanism controlling the synaptic efficacy of Ia-motoneuron transmission, is involved in the pathophysiology of spasticity. PATIENTS: Eight patients with chronic hemiplegia post-stroke presenting with lower limb spasticity and requiring botulinum toxin-type A injection in the ankle extensor muscle. METHODS: Post-activation depression of soleus H-reflex assessed as frequency-related depression of H-reflex was investigated before and 3, 6 and 12 weeks after botulinum toxin-type A injections in the triceps surae. Post-activation depression was quantified as the ratio between H-reflex amplitude at 0.5 and 0.1 Hz. RESULTS: Post-activation depression of soleus H-reflex, which is reduced on the paretic leg, was affected 3 weeks after botulinum toxin-type A injection. Depending on the residual motor capacity of the post-stroke patients, post-activation depression was either restored in patients with preserved voluntary motor control or further reduced in patients with no residual voluntary control. CONCLUSION: Botulinum toxin treatment induces synaptic plasticity at the Ia-motoneuron synapse in post-stroke paretic patients, which suggests that the effectiveness of botulinum toxin-type A in post-stroke rehabilitation might be partly due to its central effects.

Modulation of human motoneuron activity by a mental arithmetic task.

This study aimed to determine whether the performance of a mental task affects motoneuron activity. To this end, the tonic discharge pattern of wrist extensor motor units was analyzed in healthy subjects while they were required to maintain a steady wrist extension force and to concurrently perform a mental arithmetic (MA) task. A shortening of the mean inter-spike interval (ISI) and a decrease in ISI variability occurred when MA task was superimposed to the motor task. Aloud and silent MA affected equally the rate and variability of motoneuron discharge. Increases in surface EMG activity and force level were consistent with the modulation of the motor unit discharge rate. Trial-by-trial analysis of the characteristics of motor unit firing revealed that performing MA increases activation of wrist extensor SMU. It is suggested that increase in muscle spindle afferent activity, resulting from fusimotor drive activation by MA, may have contributed to the increase in synaptic inputs to motoneurons during the mental task performance, likely together with enhancement in the descending drive. The finding that a mental task affects motoneuron activity could have consequences in assessment of motor disabilities and in rehabilitation in motor pathologies.

Approximate entropy of motoneuron firing patterns during a motor preparation task.

The aim of this study was to test whether approximate entropy (ApEn) analysis provides a suitable method of detecting differences induced by a motor preparation task in time-ordered inter-spike intervals (ISIs) recorded in tonically firing motoneurons. Unlike classical methods of analyzing neuronal discharge variability, in which serial order is no taken into account, the approximate entropy (ApEn) was proposed by Pincus [Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 1991;88:2297-301] to analyze ordered series. ApEn statistic is a number assigned to an ordered series, where higher values correspond to greater serial irregularity. In the present study, the activity of 31 single motor units (SMUs) was recorded in human extensor carpi radialis muscles and the ISI durations were analyzed during the performance of a pre-cueing reaction time motor task involving a 3-s preparatory period. ApEn values were computed for each SMU during three steps of the preparatory period and during the preceding control period. Lower ApEn values, were found during preparatory period. The decrease in ApEn values, i.e., the increase in serial regularity, was monotonic from the control to the end of the preparatory period. These results show that ApEn model-independent statistics are a relevant means of detecting changes related to motor preparation in the regularity of time-ordered inter-spike intervals (ISIs).

Anticipatory changes in human motoneuron discharge patterns during motor preparation.

The influence of motor preparation on human motoneuron activity was studied by combining single motor unit recording techniques with reaction-time (RT) methods. The tonic activity of wrist extensor motor units associated with voluntary isometric contractions was analysed during preparation for a ballistic wrist extensor muscle contraction, using a time preparation procedure. Two durations of the preparatory period elapsing between the warning signal and the response signal were used in separate blocks of trials: a short preparatory period (1 s) allowing optimum time preparation, and a longer, non-optimum one (3 s). Changes in motoneuron tonic discharge patterns not associated with any changes in the force output were observed during the preparatory period, which suggests that these changes were subtle enough to prevent any changes in muscle contraction from occurring before the forthcoming movement. The changes observed were a lengthening of the mean interspike interval (ISI) and a decrease in the ISI variability. These data confirm that inhibitory mechanisms are activated during motor preparation and suggest that spinal inhibitory mechanisms are involved in the preparatory processes. The mechanisms possibly involved, such as presynaptic inhibition, disfacilitation processes or AHP conductance changes, are discussed. The fact that the preparation-induced effects on motoneuron activity were particularly prominent during the last part of the 3 s preparatory period suggests that they were probably related to the neural processes underlying temporal estimation. The anticipatory changes in motoneuron activity observed here during preparation for action provide evidence that central influences act on spinal motoneurons well before it is time to act.

Functional sparing of intrafusal muscle fibers in muscular dystrophies.

In a previous study, we showed that patients with muscular dystrophies (MDs) perceive passive movements, experience sensations of illusory movement induced by muscle tendon vibration, and have proprioceptive-regulated sways in response to vibratory stimulation applied to the neck and ankle muscle tendons. These findings argue for preserved proprioceptive functions of muscle spindles. However, it is unclear whether the function of intrafusal muscle fibers is spared, i.e., whether they retain their ability to contract when submitted to a fusimotor drive. To answer this question, we analyzed the effects of reinforcement maneuvers (mental computation and the Jendrassik maneuver) that are known to increase muscle spindle sensitivity via fusimotor drive in healthy subjects. Nine patients with different MDs participated in the study. Reinforcement maneuvers increased both the mean amplitude of the Achilles tendon reflex (187 +/- 52.9% of the mean control amplitude) and the sensitivity of muscle spindle afferents to imposed movements of the ankle. The same reinforcement maneuvers failed to alter the amplitude of the Hoffmann reflex in the triceps surae muscle. These results suggest that the intrafusal muscle fibers preserve their contractile abilities in slowly progressive MDs. The reasons for a differential impairment of intrafusal and extrafusal muscle fibers and the clinical implications of the present results are discussed.

Changes in the inhibitory control exerted by the antagonist Ia afferents on human wrist extensor motor units during an attention-demanding motor task.

The aim of this study was to determine the extent to which an attention-demanding visuomotor task affects the strength of the inhibitory control exerted by the wrist flexor group Ia afferents on the wrist extensor motoneurons. Effects of median nerve stimulation on the tonic activity of wrist extensor single motor units were analyzed in terms of the interspike interval (ISI) lengthening. Results show that the inhibitory effects exerted by the antagonistic group Ia afferents were significantly enhanced when the wrist extensor motoneurons were involved in an attention-demanding task. Enhanced inhibition from antagonist afferents may reflect task-related changes in the excitability of the di- and/or polysynaptic pathways mediating reciprocal inhibition due to either the action of descending inputs and/or an increase in the efficiency of the Ia inputs to the premotoneuronal inhibitory interneurons. Modulation of the inhibition exerted by proprioceptive antagonist afferents may be one of the processes which contribute to the fine adjustment of the wrist muscle force output required in fine handling tasks.

Proprioceptive control of human wrist extensor motor units during an attention-demanding task.

The responsiveness of the tonically firing single motor units (SMU) to Ia afferent volleys elicited by either mechanical (T-reflex) or electrical nerve stimulation (H-reflex) was tested in the extensor carpi radialis muscle (ECR) while the subjects were maintaining a steady wrist extension force using visual feedback set either at low or high gain. The aim was to determine whether the proprioceptive control of tonic motoneuronal activity depends on the level of attentiveness required by the behavioural context. The response probability of the SMUs to tendon taps was significantly higher (p<0.0001) and that to electrical nerve stimulation was lower (p<0.001) during the more demanding task. Since these changes in SMU responsiveness were not accompanied by any differences in either the motor unit firing patterns or the mean levels of EMG muscle activity, it can be concluded that there were no attention-related changes in the net excitatory drive to the ECR motoneurons. These results are consistent with the idea that fusimotor sensitization of the muscle spindle may have occurred in the more demanding task: an increase in the mechanical sensitivity of the muscle spindles would certainly account for both the T-reflex facilitation and the H-reflex depression observed. The attention-demanding task therefore seemed to involve an independent fusimotor drive activation process. The results of this study suggest that an adaptation of the fusimotor system occurs in humans, depending on the levels of attention and accuracy required to perform the ongoing motor task, as previously reported to occur in animals.

The influence of increased muscle spindle sensitivity on Achilles tendon jerk and H-reflex in relaxed human subjects.

Whether the fusimotor system contributes to reflex gain changes during reinforcement maneuvers is re-examined in the light of new data. Recently, from direct recordings of spindle afferent activity originating from ankle flexor muscles, we showed that mental computation increased the muscle spindle mechanical sensitivity in completely relaxed human subjects without concomitant alpha-motoneuron activation, providing evidence for selective fusimotor drive activation. In the present study, the effects of mental computation were investigated on monosynaptic reflexes elicited in non-contracting soleus muscle either by direct nerve stimulation (Hoffmann reflex, H) or by tendon tap (Tendinous reflex, T). The aim was to relate the time course of the changes in reflex size to the increase in spindle sensitivity during mental task in order to explore whether fusimotor activation can influence the size of the monosynaptic reflex. The results show changes in reflex amplitude that parallel the increase in muscle spindle sensitivity. When T-reflex is consistently facilitated during mental effort, the H-reflex is either depressed or facilitated, depending on the subjects. These findings suggest that the increased activity in muscle spindle primary endings may account for mental computation-induced changes in both tendon jerk and H-reflex. The facilitation of T-reflex is attributed to the enhanced spindle mechanical sensitivity and the inhibition of H-reflex is attributed to post-activation depression following the increased Ia ongoing discharge. This study supports the view that the fusimotor sensitization of muscle spindles is responsible for changes in both the mechanically and electrically elicited reflexes. It is concluded that the fusimotor drive contributed to adjustment of the size of tendon jerk and H-reflex during mental effort. The possibility that a mental computation task may also operate by reducing the level of presynaptic inhibition is discussed on the basis of H-reflex facilitation.