Hans Hultborn

Bistability of alpha‐motoneurones in the decerebrate cat and in the acute spinal cat after intravenous 5‐hydroxytryptophan.

1. In the preceding paper (Crone, Hultborn, Kiehn, Mazieres & Wigström, 1988) it was shown that a short‐lasting synaptic excitation (‘on’ stimulus) of extensor motoneurones (primarily triceps surae) in the decerebrate cat often resulted in a maintained excitability increase, which could be reset by a short‐lasting inhibitory stimulus train (‘off’ stimulus). In the present experiments intracellular recording from triceps surae motoneurones and the electroneurogram (ENG activity) from triceps surae nerve branches were performed in parallel. 2. Sustained firing of individual triceps surae motoneurones was most often recorded in parallel with the maintained ENG activity following a synaptic ‘on’ stimulus. When the motoneurone was silenced, by a hyperpolarizing current through the microelectrode, there was no sign of on‐going synaptic excitation during the maintained ENG activity following an ‘on’ stimulus. It was therefore suggested that voltage‐dependent intrinsic properties of the motoneurones themselves could be responsible for the maintained firing. 3. In confirmation of this hypothesis it was found that short‐lasting depolarizing current pulses through the recording microelectrode could trigger a self‐sustained firing in the motoneurone provided that the bias current (i.e. the holding potential) was kept within certain limits. Hyperpolarizing current pulses terminated the firing. When the spike‐generating mechanism was inactivated (by long‐lasting excessive depolarization) similar depolarizing and hyperpolarizing current pulses could initiate and terminate plateau potentials in the motoneurones. By grading the depolarizing current pulses it was found that the plateau potentials were of all‐or‐none character, typically around 10 mV in amplitude. The two levels of excitability which can be triggered by short‐lasting excitation and inhibition of the motoneurones is referred to as ‘bistable’ behaviour of the motoneurones. 4. After an acute spinal transection, in the unanaesthetized cat, the bistable behaviour of the motoneurones disappeared. However, it reappears following intravenous injection of the serotonin precursor 5‐hydroxytryptophan (50‐120 mg/kg). 5. Individual triceps surae motor units were recorded by selective EMG electrodes during tonic stretch reflexes in the decerebrate preparations. Based on an analysis of their firing pattern during lengthening and shortening (or vibration) of the muscle it is suggested that plateau potentials in motoneurones are recruited during the tonic stretch reflex. Furthermore, it is argued that a quantitatively important part of the depolarization of motoneurones during the tonic stretch reflex indeed originates from these plateau potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

Proprioceptive input resets central locomotor rhythm in the spinal cat

SummaryThe reflex regulation of stepping is an important factor in adapting the step cycle to changes in the environment. The present experiments have examined the influence of muscle proprioceptors on centrally generated rhythmic locomotor activity in decerebrate unanesthetized cats with a spinal transection at Th12. Fictive locomotion, recorded as alternating activity in hindlimb flexor and extensor nerves, was induced by administration of nialamide (a monoamine oxidase inhibitor) and L-DOPA. Brief electrical stimulation of group I afferents from knee and ankle extensors were effective in resetting fictive locomotion in a coordinated fashion. An extensor group I volley delivered during a flexor burst would abruptly terminate the flexor activity and initiate an extensor burst. The same stimulus given during an extensor burst prolonged the extensor activity while delaying the appearance of the following flexor burst. Intracellular recordings from motoneurones revealed that these actions were mediated at premotoneuronal levels resulting from a distribution of inhibition to centres generating flexor bursts and excitation of centres generating extensor bursts. These results indicate that extensor group I afferents have access to central rhythm generators and suggest that this may be of importance in the reflex regulation of stepping. Experiments utilizing natural stimulation of muscle receptors demonstrate that the group I input to the rhythm generators arises mainly from Golgi tendon organ Ib afferents. Thus an increased load of limb extensors during the stance phase would enhance and prolong extensor activity while simultaneously delaying the transition to the swing phase of the step cycle.

Sensitivity of monosynaptic test reflexes to facilitation and inhibition as a function of the test reflex size: a study in man and the cat

SummaryIn parallel experiments on humans and in the cat it was investigated how the sensitivity of monosynaptic test reflexes to facilitation and inhibition varies as a function of the size of the control test reflex itself. In man the monosynaptic reflex (the Hoffmann reflex) was evoked in either the soleus muscle (by stimulation of the tibial nerve) or the quadriceps muscle (by stimulation of the femoral nerve). In the decerebrate cat monosynaptic reflexes were recorded from the nerves to soleus and medial gastrocnemius muscles; they were evoked by stimulation of the proximal ends of the sectioned L7 and S1 dorsal roots. Various excitatory and inhibitory spinal reflex pathways were used for conditioning the test reflexes (e.g. monosynaptic Ia excitation, disynaptic reciprocal inhibition, cutaneous inhibition, recurrent inhibition, presynaptic inhibition of the Ia fibres mediating the test reflex). It was shown that the additional number of motoneurones recruited in a monosynaptic test reflex by a constant excitatory conditioning stimulus was very much dependent on the size of the test reflex itself. This dependency had the same characteristic pattern whatever the conditioning stimulus. With increasing size of the test reflex the number of additionally recruited motoneurones first increased, then reached a peak (or plateau) and finally decreased. A similar relation was also seen with inhibitory conditioning stimuli. The basic physiological factors responsible for these findings are discussed. Finally, the implications for the interpretation of experiments in man with the H-reflex technique are considered.

Assessing changes in presynaptic inhibition of I a fibres: a study in man and the cat.

1. A method to assess changes in presynaptic inhibition of I a afferent terminals in man is proposed. The soleus H reflex was facilitated by a heteronymous I a volley from quadriceps and the amount of reflex facilitation was used to estimate the size of the conditioning I a excitatory post‐synaptic potential (e.p.s.p.). It is argued that the size of this e.p.s.p. as measured by the resulting amount of reflex facilitation reflects the amount of presynaptic inhibition on the corresponding I a fibres. A decrease in the reflex facilitation may then be ascribed to an increase in presynaptic inhibition of the I a fibres mediating the conditioning volley. 2. That the heteronymous I a facilitation from quadriceps to soleus is caused by a purely monosynaptic e.p.s.p. is a prerequisite for the validity of the method. Experimental evidence is therefore given in an Appendix that in man the earliest part (first 0.5 ms) of this heteronymous I a facilitation is mediated through a monosynaptic pathway. Evidence is also given that this earliest facilitation is not yet contaminated by any polysynaptic effects from I a or I b afferents. 3. The validity of the method was established in animal experiments in which presynaptic inhibition of I a fibres and post‐synaptic events in motoneurones could be assessed by direct tests. It was found that the amount of test reflex facilitation produced by a conditioning I a volley was decreased when I a fibres were subjected to presynaptic inhibition but remained unchanged when the motoneurone pool in which the test reflex was elicited received pure post‐synaptic inhibition. 4. In man, presynaptic inhibition of I a fibres was evoked by a short‐lasting (three shocks at 200 Hz) vibration applied to the tibialis anterior tendon. Such a vibratory burst reduced the efficiency of the heteronymous I a volley in facilitating the soleus H reflex. By contrast, during a pure post‐synaptic inhibition of soleus motoneurones the efficiency of the conditioning volley in facilitating the test reflex remained unchanged. It is therefore argued that the amount of heteronymous I a facilitation can indeed be used to assess the amount of ongoing presynaptic inhibition exerted onto heteronymous I a fibres from the quadriceps muscle to soleus motoneurones. 5. The short‐lasting tibialis anterior vibration used here evoked a long‐lasting (300‐500 ms) depression of soleus and quadriceps H reflexes.(ABSTRACT TRUNCATED AT 400 WORDS)

On the mechanism of the post-activation depression of the H-reflex in human subjects

It was demonstrated that the soleus H-reflex was depressed for more than 10 s following a preceding passive dorsiflexion of the ankle joint. This depression was caused by activation of large-diameter afferents with receptors located in the leg muscles, as an ischaemic block of large-diameter fibres just below the knee joint abolished the depression, whereas a similar block just proximal to the ankle joint was ineffective. The depression of the H-reflex was not caused by changes in motoneuronal excitability, as motor-evoked potentials by magnetic brain stimulation were not depressed by the same passive dorsiflexion. Therefore it was concluded that the long-lasting depression is due to mechanisms acting at presynaptic level. The transmission of the monosynaptic Ia excitation from the femoral nerve to soleus motoneurones was not depressed by the ankle dorsiflexion. The depression thus seems to be confined to those afferents that were activated by the conditioning dorsiflexion. In parallel experiments on decerebrate cats, more invasive methods have complemented the indirect techniques used in the experiments on human subjects. A similar long-lasting depression of triceps surae monosynaptic reflexes was evoked by a preceding conditioning stimulation of the triceps surae Ia afferents. This depression was accompanied by a reduction of the monosynaptic Ia excitatory postsynaptic potential recorded intracellularly in triceps surae motoneurones, but not by changes in the input resistance or membrane potential in the motoneurones. Stimulation of separate branches within the triceps surae nerve demonstrated that the depression is confined to those afferents that were activated by the conditioning stimulus. This long-lasting depression was not accompanied by a dorsal root potential. It is concluded that the long-lasting depression is probably caused by a presynaptic effect, but different from the “classical” GABAergic presynaptic inhibition which is widely distributed among afferent fibres and accompanied by dorsal root potentials. It is more probably related to the phenomenon of a reduced transmitter release from previously activated fibres, i.e. a homosynaptic post-activation depression. The consequences of this post-activation depression for the interpretation of results on spinal mechanisms during voluntary movements in man are discussed.

Reciprocal Ia inhibition between ankle flexors and extensors in man.

1. Reciprocal inhibition between antagonist muscle groups at the ankle has been investigated in sixty healthy subjects. Hoffmann reflexes (H reflexes) in the soleus and tibialis anterior muscles were used to assess changes in reciprocal inhibition evoked by electrical stimulation of antagonist muscle nerves. 2. Inhibition of the soleus H reflex was evoked by a single conditioning stimulus to the common peroneal nerve, and inhibition of the tibialis anterior H reflex was elicited by one conditioning stimulus to the posterior tibial nerve. Symmetrical central connections between the antagonist flexors and extensors were assumed and under this assumption the central delay for the inhibition, in addition to the delay for monosynaptic Ia excitation, was calculated to be about 1 ms. The inhibition was evoked by weak stimuli to the nerves from antagonist muscle groups; the threshold for the inhibition was around 0.6 X threshold for a direct motor response (M‐threshold). Furthermore, tendon taps to the Achilles tendon facilitated the soleus H reflex and inhibited the tibialis anterior reflex at short latencies. The short central delay, the low electrical threshold and the.actions of Achilles tendon taps strongly suggest that the early reciprocal inhibition is homologous to the disynaptic Ia inhibition previously studied in animal experiments. 3. With the test soleus H reflex kept at 15‐25% of the maximum directly evoked motor response (M‐response) and the strength of the conditioning peroneal nerve stimulation kept at 1.0 X M‐threshold, the inhibition from the peroneal nerve ranged between 0 and 40% (mean, 14.9%) at rest. 4. Changes in the amount of reciprocal inhibition from the peroneal nerve were studied both during tonic and dynamic dorsi‐ and plantarflexion. During tonic dorsiflexion there was no significant change of inhibition as compared to rest, while inhibition decreased during tonic plantarflexion. However, during ramp‐and‐hold dorsiflexion there was a transient increase in reciprocal inhibition of the soleus H reflex. This increase in inhibition from the peroneal nerve could be seen 50 ms prior to the onset of contraction. The increase in inhibition before and at the very beginning of the contraction cannot be due to sensory feed‐back during contraction, but must depend on a supraspinal control of the spinal cord. 5. At conditioning‐test intervals of 4‐6 ms, the inhibition of the soleus H reflex from the peroneal nerve was considerably larger during tonic dorsiflexion than at rest. Thus, tonic dorsiflexion revealed an inhibition with long latency from the peroneal nerve, which was not seen at rest.(ABSTRACT TRUNCATED AT 400 WORDS)

Transmission in a locomotor-related group Ib pathway from hindlimb extensor muscles in the cat

It has been previously shown that phasic stimulation of group I afferents from ankle and knee extensor muscles may entrain and/or reset the intrinsic locomotor rhythm; these afferents are thus acting on motoneurones through the spinal rhythm generators. It was also concluded that the major part of these effects originates from Golgi tendon organ Ib afferents. Transmission in this pathway to lumbar motoneurones has now been investigated during fictive locomotion in spinal cats injected with nialamide and l-DOPA, and in decerebrate cats with stimulation of the mesencephalic locomotor region. In spinal cats injected with nialamide and l-DOPA, it was possible to evoke long-latency, long-lasting reflexes upon stimulation of high threshold afferents before spontaneous fictive locomotion commenced. During that period, stimulation of ankle and knee extensor group I afferents evoked oligosynaptic excitation of extensor motoneurones, rather than the “classical” Ib inhibition. Furthermore, a premotoneuronal convergence (spatial facilitation) between this group I excitation and the crossed extensor reflex was established. During fictive locomotion, in both preparations, the transmission in these group I pathways was phasically modulated within the step cycle. During the flexor phase, the group I input cut the depolarised (active) phase in flexor motoneurones and evoked EPSPs in extensor motoneurones; during the extensor phase, the group I input evoked smaller EPSPs in extensor motoneurones and had virtually no effect on flexor motoneurones. The above results suggest that the group I input from extensor muscles is transmitted through the spinal rhythm generator and more particularly, through the extensor “half-centre”. The locomotor-related group I excitation had a central latency of 3.5–4.0 ms. The excitation from ankle extensors to ankle extensors remained after a spinal transection at the caudal part of L6 segment; the interneurones must therefore be located in the L7 and S1 spinal segments. Candidate interneurones for mediating these actions were recorded extracellularly in lamina VII of the 7th lumbar segment. Responses to different peripheral nerve stimulation (high threshold afferents and group I afferents bilaterally) were in concordance with the convergence studies in motoneurones. The interneurones were rhythmically active in the appropriate phases of the fictive locomotor cycle, as predicted by their response patterns. The synaptic input to, and the projection of these candidate interneurones must be fully identified before their possible role as components of the spinal locomotor network can be evaluated.

The spinal pathophysiology of spasticity - from a basic science point of view

Spasticity is a term, which was introduced to describe the velocity‐sensitive increased resistance of a limb to manipulation in subjects with lesions of descending motor pathways. This distinguishes spasticity from the changes in passive muscle properties, which are often seen in these patients, but are not velocity‐sensitive. Increased excitability of the stretch reflex is thus a central component of the definition of spasticity. This review describes changes in cellular properties and transmission in a number of spinal reflex pathways, which may explain the increased stretch reflex excitability. The review focuses mainly on results derived from the use of non‐invasive electrophysiological techniques, which have been developed during the past 20–30 years to investigate spinal neuronal networks in human subjects, but work from animal models is also considered. The reflex hyperexcitability develops over several months following the primary lesion and involves adaptation in the spinal neuronal circuitries caudal to the lesion. In animal models, changes in cellular properties (such as ‘plateau potentials’) have been reported, but the relevance of these changes to human spasticity has not been clarified. In humans, numerous studies have suggested that reduction of spinal inhibitory mechanisms (in particular that of disynaptic reciprocal inhibition) is involved. The inter‐subject variability of these mechanisms and the lack of objective quantitative measures of spasticity have impeded disclosure of a clear causal relationship between the alterations in the inhibitory mechanisms and the stretch reflex hyperexcitability. Techniques which make such a quantitative measure possible as well as longitudinal studies where development of reflex excitability and changes in the inhibitory mechanisms are followed over time are in great demand.

Plateau potentials in alpha‐motoneurones induced by intravenous injection of L‐dopa and clonidine in the spinal cat.

1. Intracellular recordings were made from lumbar alpha‐motoneurones in unanaesthetized decerebrate acute spinal cats. The response of motoneurones to direct current pulse injection or synaptic excitation was investigated following intravenous injection of L‐beta‐3,4‐dihydroxyphenylalanine (L‐DOPA, 20‐120 mg/kg) alone, nialamide (10‐50 mg/kg) and L‐DOPA or clonidine (0.5‐1 mg/kg). 2. The response properties of motoneurones were tested with rectangular and triangular current waveforms. Before L‐DOPA treatment motoneuronal firing during a rectangular current pulse is characterized by an initial high firing frequency which rapidly decreases to a lower steady‐state firing which is maintained only for the duration of the pulse. Following administration of L‐DOPA an acceleration in firing frequency is apparent following the initial adaptation seen with rectangular current pulses. A transient after‐depolarization or an after‐discharge often followed the termination of the pulse. The frequency‐current relation in response to a triangular current injection changed from a clockwise to a counter‐clockwise hysteresis after L‐DOPA treatment (i.e. after L‐DOPA the firing frequency was higher for any given current during the descending phase than during the ascending phase of the triangular waveform). 3. Firing acceleration during and self‐sustained firing after rectangular current pulses and counter‐clockwise hysteresis of firing frequency with triangular current pulses are causally related to the presence of plateau potentials, which can be directly visualized after inactivation of the spikes. Plateau potentials in motoneurones could be generated by short‐lasting intracellular depolarizing current pulses or brief excitatory synaptic inputs and terminated by short‐lasting hyperpolarizing current pulses or brief inhibitory synaptic inputs. Plateau potentials were demonstrated in flexor and extensor motoneurones. 4. All bistable properties described in the preceding paragraphs following L‐DOPA administration could also be seen after administration of the alpha‐receptor agonist clonidine. 5. Slow rhythmic oscillations of the membrane potential (7.5‐10 Hz) were seen superimposed on plateau potentials in a few cells after administration of L‐DOPA and clonidine. The oscillations had an amplitude in the range 10‐20 mV and represent the expression of an intrinsic property of the motoneurone. 6. It is demonstrated that plateau potentials in the motoneurones contribute to the late long‐lasting reflexes observed in L‐DOPA‐treated spinal cats. 7. It is concluded that L‐DOPA (and clonidine) change the response properties of the motoneurones in an analogous way to 5‐hydroxy‐DL‐tryptophan (5‐HTP).(ABSTRACT TRUNCATED AT 400 WORDS)

Maintained changes in motoneuronal excitability by short‐lasting synaptic inputs in the decerebrate cat.

1. During investigation of the tonic stretch reflex in the unanaesthetized decerebrate cat we observed that a short train of impulses in Ia afferents from the soleus muscle (or its synergists) may cause a prolonged activity in the soleus muscle as judged by EMG and tension recordings. This excitability increase, which outlasted the stimulus train, could stay virtually constant during long periods (even minutes), but could be terminated at any time by a train of impulses in, for example, the peroneal nerve. 2. Gradation of the strength of stimulation and the duration of the train of impulses show that the amount of maintained excitability increase depends‐within some limits‐on the total amount of Ia impulses. 3. In paralysed preparations a short train of impulses in Ia afferents from any part of the triceps surae, caused a maintained increase of the efferent activity in the nerves to triceps surae and a maintained increase of the triceps surae monosynaptic test reflex. These experiments demonstrate the existence of a central mechanism (in the spinal cord and/or the brain stem), which is responsible for the maintained excitability increase seen in motoneurones to the homonymous and synergic muscles. 4. In acute spinal preparations it was not possible to demonstrate any long‐lasting excitability increase by a train of Ia impulses. Following intravenous administration of the serotonin precursor 5‐hydroxytryptophan, mimicking the tonic activity of these pathways in the decerebrate state, it was again possible to elicit the long‐lasting excitability increase by a train of impulses in Ia afferents. A subsequent I.V. injection of methysergide (a serotonin receptor blocker) abolished the long‐lasting excitability increase. This set of experiments demonstrates that the basic mechanism responsible for the maintained excitability increase is located at segmental level, and involves serotonergic systems. 5. It was demonstrated that activation of several ipsilateral and crossed reflex pathways by trains of impulses in cutaneous or high‐threshold muscle afferents could trigger a maintained excitability increase of those motoneurone pools which were activated by the stimulation. Trains of stimuli to facilitatory regions in the brain stem could also cause a long‐lasting excitability increase of motoneurones. Furthermore, activation of all reflex pathways which mediate postsynaptic inhibition to a motor nucleus (including recurrent inhibition via Renshaw cells) could terminate the prolonged excitability increase of that particular motor nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)