André Fabio Kohn

Presynaptic inhibition compared with homosynaptic depression as an explanation for soleus H-reflex depression in humans

Abstract The H-reflex is depressed for seconds if elicited following a single H-reflex or train of H-reflexes. Presynaptic inhibition from flexor afferents (tibialis anterior) onto soleus Ia afferents elicited by either single or trains of stimuli had no effect on the soleus H-reflex on a time scale of seconds. Postsynaptic inhibition was also excluded by magnetic stimulation tests that showed that the excitability of the motoneuron pool was not changed at latencies within a range of seconds. Homosynaptic depression localized at the presynaptic terminal seems to be the mechanism behind the H-reflex depression in humans.

Simulation system of spinal cord motor nuclei and associated nerves and muscles, in a Web-based architecture.

A Web-based simulation system of the spinal cord circuitry responsible for muscle control is described. The simulator employs two-compartment motoneuron models for S, FR and FF types, with synaptic inputs acting through conductance variations. Four motoneuron pools with their associated interneurons are represented in the simulator, with the possibility of inclusion of more than 2,000 neurons and 2,000,000 synapses. Each motoneuron action potential is followed, after a conduction delay, by a motor unit potential and a motor unit twitch. The sums of all motor unit potentials and twitches result in the electromyogram (EMG), and the muscle force, respectively. Inputs to the motoneuron pool come from populations of interneurons (Ia reciprocal inhibitory interneurons, Ib interneurons, and Renshaw cells) and from stochastic point processes associated with descending tracts. To simulate human electrophysiological experiments, the simulator incorporates external nerve stimulation with orthodromic and antidromic propagation. This provides the mechanisms for reflex generation and activation of spinal neuronal circuits that modulate the activity of another motoneuron pool (e.g., by reciprocal inhibition). The generation of the H-reflex by the Ia-motoneuron pool system and its modulation by spinal cord interneurons is included in the simulation system. Studies with the simulator may include the statistics of individual motoneuron or interneuron spike trains or the collective effect of a motor nucleus on the dynamics of muscle force control. Properties associated with motor-unit recruitment, motor-unit synchronization, recurrent inhibition and reciprocal inhibition may be investigated.

Vibratory noise to the fingertip enhances balance improvement associated with light touch

Light touch of a fingertip on an external stable surface greatly improves the postural stability of standing subjects. The hypothesis of the present work was that a vibrating surface could increase the effectiveness of fingertip signaling to the central nervous system (e.g., by a stochastic resonance mechanism) and hence improve postural stability beyond that achieved by light touch. Subjects stood quietly over a force plate while touching with their right index fingertip a surface that could be either quiescent or randomly vibrated at two low-level noise intensities. The vibratory noise of the contact surface caused a significant decrease in postural sway, as assessed by center of pressure measures in both time and frequency domains. Complementary experiments were designed to test whether postural control improvements were associated with a stochastic resonance mechanism or whether attentional mechanisms could be contributing. A full curve relating body sway parameters and different levels of vibratory noise resulted in a U-like function, suggesting that the improvement in sway relied on a stochastic resonance mechanism. Additionally, no decrease in postural sway was observed when the vibrating contact surface was attached to the subject’s body, suggesting that no attentional mechanisms were involved. These results indicate that sensory cues obtained from the fingertip need not necessarily be associated with static contact surfaces to cause improvement in postural stability. A low-level noisy vibration applied to the contact surface could lead to a better performance of the postural control system.

H-reflexes of different sizes exhibit differential sensitivity to low frequency depression

The amplitude of the H-reflex declines when activated repetitively. The magnitude of decline is greater when the amplitude of the H-reflex is small. To explore whether pre- or postsynaptic factors contribute to the differences observed in H-reflexes of different sizes, changes in the amplitude of H-reflexes of different sizes were measured during a train of stimulation in 10 normal subjects. Amplitudes of different sizes were obtained using differing stimulus intensities or during superimposed contraction, two manipulations which differently affect the number of active afferents and the excitation of the motoneuron pool. Small amplitude H-reflexes depressed to a lower plateau than larger H-reflexes and superimposed contraction did not alleviate the depression during each train. Nearly all the decline in larger amplitude H-reflexes occurred in a component that was in common with smaller amplitude H-reflexes. This suggests that the depressibility of the earliest activated units is greater than later activated units in H-reflexes and that the magnitude of decline is affected by prior activity as well as size.

Presynaptic irregularity and pacemaker inhibition

It is known (e.g., Perkel et al., 1964) that when a pacemaker neuron elicits IPSPs in another, there are domains called “paradoxical segments” where in the steady-state i) faster inhibitory discharges determine faster inhibited ones, and ii) pre- and postsynaptic spikes are “locked” in an invariant forward-and-backward positioning in time, spikes alternating in the ratios 1:1 (1 pere for 1 postsynaptic), 1:2, 2:1..., that are also the slopes of the synaptic rate-transformation. The present project examined the matter further in the inhibitory synapse upon the crayfish tonic stretch receptor neuron, confirming the above. In addition it showed that locking and alternation existed also in the segments interposed between the 1:2, 1:1 and 2:1 paradoxical segments, even though they were not as marked and apparent, and that when tests were close to each other their order became influential and hysteresis-like phenomena appeared. The main finding was that paradoxical rate-relations, locking and alternation persisted when the presynaptic train was irregularized up to interval coefficients of variation of around 0.20 (Figs. 2–5). Therefore, both phenomena may not simply be laboratory curiosities, but also have a role in natural operation where probably a substantial population of neurons exhibits that kind of irregularity. As presynaptic irregularity increased, the paradoxical segment slopes and widths decreased and locking and alternation became less clear-cut. With CVs of about 0.20, only a relatively narrow 1:1 paradoxical segment with about O slope and little locking and alternation remained (Figs. 2b, 3g, 4right, 5third row). With larger CVs, the rate relation decreased monotonically and there was no locking nor alternation (Figs. 2e, 3h, 5bottom row). The postsynaptic discharge was more regular and had fewer changes in the number of presynaptic spikes per post-synaptic interval within paradoxical segments (particularly in their centers) than in segments interposed between them (left vs. right-hand columns in Figs. 5, 6; Fig. 7): the contrast, remarkable for regular stimuli, attenuated as variability increased. The following conclusions are relevant to coding of spike trains across a synapse with IPSPs. i) With fairly regular discharges, the same postsynaptic rate may result from several presynaptic ones (e.g., may result from rates in the 1:1 and 2:1 paradoxical segments and in the interposed one, Fig.2): in some cases but not others, the precise presynaptic rate can be identified on the basis of postsynaptic CVs, interval histograms and cycle slips. ii) A small rate change in a regular presynaptic discharge will have very different postsynaptic consequences depending on where it happens: if across a paradoxical-interposed boundary, for instance, it will cause remarkable rate, pattern and correlation changes. iii) The trans-synaptic mapping of variability involves an increase for the more regular presynaptic discharges and a decrease for the more irregular ones. iv) The postsynaptic discharge was slower with IPSPs than without in most cases; however, when the control discharge was weak or absent, IPSPs accelerated it. Results are relevant also to the operation of periodically performing systems that involve neuronal correlates, indicating that it is necessary in every case to ask whether zigzag relations and locking occur. The “delay function” plots the arrival time of an IPSP (or IPSP burst) relative to the last postsynaptic spike, i.e., the “phase” (Φ in Fig. 1b), against the interval lengthening produced, i.e., the “delay” (δ). In all cases, most points clustered around a straight line (Fig. 8), whose slope and ordinate intercept were in the 0.43–0.87 and the 0.02–0.52 ranges, respectively, for single IPSPs. The slope reflects how the IPSP effectiveness depends on when it arrives in the cycle; the intercept reflects the IPSP effectiveness. Large phases often showed “aberrant” points whose ordinates were either large (and having special formal implications), or very small (perhaps reflecting conduction and synaptic delays), or clustered around a second straight segment with a large negative slope (when spontaneous rates were low) (Fig. 8c). Delay functions for widely separated pairs of IPSPs could be multi-valued, points clustering around 2 or 3 parallel straight lines. A mathematical model of pacemaker inhibitory synaptic interactions (Segundo, 1979) agreed with this embodiment insofar as some postulated properties are concerned (e.g., regular discharge, interval lengthening by IPSPs, linear delay functions with slopes around 0.7) and as to the main aspects of the preparations behavior (i.e., zigzag rate relations and locking), but not in terms of some aspects of the postulates (e.g., interval variability, rebound) or behavior (e.g., segment boundaries, jitter in the locking, and hysteresis). The model was judged to be on the balance satisfactorily realistic.

Spinal Mechanisms May Provide a Combination of Intermittent and Continuous Control of Human Posture: Predictions from a Biologically Based Neuromusculoskeletal Model

Several models have been employed to study human postural control during upright quiet stance. Most have adopted an inverted pendulum approximation to the standing human and theoretical models to account for the neural feedback necessary to keep balance. The present study adds to the previous efforts in focusing more closely on modelling the physiological mechanisms of important elements associated with the control of human posture. This paper studies neuromuscular mechanisms behind upright stance control by means of a biologically based large-scale neuromusculoskeletal (NMS) model. It encompasses: i) conductance-based spinal neuron models (motor neurons and interneurons); ii) muscle proprioceptor models (spindle and Golgi tendon organ) providing sensory afferent feedback; iii) Hill-type muscle models of the leg plantar and dorsiflexors; and iv) an inverted pendulum model for the body biomechanics during upright stance. The motor neuron pools are driven by stochastic spike trains. Simulation results showed that the neuromechanical outputs generated by the NMS model resemble experimental data from subjects standing on a stable surface. Interesting findings were that: i) an intermittent pattern of muscle activation emerged from this posture control model for two of the leg muscles (Medial and Lateral Gastrocnemius); and ii) the Soleus muscle was mostly activated in a continuous manner. These results suggest that the spinal cord anatomy and neurophysiology (e.g., motor unit types, synaptic connectivities, ordered recruitment), along with the modulation of afferent activity, may account for the mixture of intermittent and continuous control that has been a subject of debate in recent studies on postural control. Another finding was the occurrence of the so-called “paradoxical” behaviour of muscle fibre lengths as a function of postural sway. The simulations confirmed previous conjectures that reciprocal inhibition is possibly contributing to this effect, but on the other hand showed that this effect may arise without any anticipatory neural control mechanism.

A model of excitatory synaptic interactions between pacemakers. Its reality, its generality, and the principles involved

This is a model of the steady-state influence of one pacemaker neuron upon another across a synapse with EPSPs. Its postulates require firstly the spontaneous regularity of both cells, whose intervals are E and N, respectively. In addition, they require a special shortening or negative “delay” of the interspike interval by one or more EPSPs, with a V-shaped dependence of the delay on the position or “phase” of the EPSPs in the interval; the minimum of the delay function corresponds to the earliest EPSP arrival phase (λ) that triggers a spike immediately. Finally, they impose on the variables certain bounds. The models behavior has two main features. The first is a zig-zag relationship with an overall increasing trend between the steady-state pre- and post-synaptic discharge intensities (Fig. 7). The zig-zag is formed predominantly, if not exclusively, by segments with positive slopes that are rational fractions. Passage from one such segment to others is negatively-sloped (“paradoxical”), involving staggered positively-sloped segments whose details are unclear for weak presynaptic discharges and discontinuities for intense discharges. The same postsynaptic intensity may result from several presynaptic ones; the maximum postsynaptic intensity may reflect refractoriness, or the earliest instants of immediate triggering. The second main feature is the “locking” of the discharges in an invariant forward and backward temporal relation. With at most one EPSP per postsynaptic spike, locking is always present. If the presynaptic interval E is in the closed {rN+λ,(r+1)N} range, locking is 1:r+1, either stable at a greater-than-λ phase or unstable at a smaller one; arrivals at integral multiples of N do not affect the postsynaptic intensity. If E is in {rN, rN+λ} (r>0), locking is at other ratios (e.g., 2:3) and less apparent. With more than one EPSP per spike, when E is below bounds that depend on the interspike interval and the point of earliest triggering, locking happens in the simple s′:1 ratio (s′=2,3, ...) and is stable; when E is above those bounds, there are E ranges where locking is in other ratios (e.g., 3:2) and ranges where behavior is unclear. The validity of any model is based jointly upon an a priori judgment as to whether postulates depart reasonably little from nature, and upon an a posteriori experimental comparison of modelled and real behaviors. The models domain of applicability depends on the specific embodiment, each of the latter tolerating characteristically each departure. The present model will be evaluated in the crayfish stretch-receptor neuron (Diez-Martínez et al., in preparation). The model is applicable to any physical system that complies with its postulates, and evidence compatible with this notion is available in many disparate fields. It illustrates the modelling path to a scientific proposition, other paths being inference from experimentation, or deduction from premises acceptable at other approach levels (in this case, for example, from that of synaptic mechanisms). The periodicity postulates set this model within the category of those for oscillators. The notion of an oscillator has a far broader applicability than appears at first sight, since all physically realizable systems have some predominant output frequency, i.e., to a certain extent are oscillators.

Pervasive locking, saturation, asymmetric rate sensitivity and double-valuedness in crayfish stretch receptors

The correspondence between afferent discharges and sinusoidal length modulations (0.2–10 cps, under 10% of the natural length variations) was studied in isolated fast-adapting stretch receptor organs (FAO) of crayfish, largely using average displays of rate vs. length (or derivatives) along the cycle. Rate modulations were greatest during early cycles and then stabilized, an initial adjustment remindful of mechanical preconditioning. Responses to stimulation in the FAO, as in the slowly-adapting organs (SAO) and possibly other receptors, exhibit the following features, all striking because of their magnitude and ubiquity. i) A zig-zag overall afferent rate vs. stimulus frequency graph with positively and negatively sloped segments. This precludes the straighforward use of Bode plots. ii) Marked non-linearities as an obvious stimulus-response locking in the positively sloped segments, a double-valuedness with one rate while stretching and another while shortening, a lower-limit saturation with the receptor silent for more than half a cycle, and an asymmetric rate sensitivity. iii) Clear-cut discharge leads relative to the stimulus at low frequencies and lags at high ones. The FAO responds worse than the SAO to low frequencies, and better to high ones; it is locked 1-to-1 in a much broader range (e.g., 3–100 vs. 1–3 cps). All features were strongly frequency-dependent. With higher frequencies: i) the number of impulses per cycle fell from several to just one and finally to one every several cycles at higher values; ii) the two values of each length approached one another usually but not always; iii) the silent proportion of the cycle increased; and iv) the rate sensitivity changed. Each feature can arise in principle at any of the transduction stages from length to discharge: the mechanical transduction from length to dendritic deformation, and the encoder one from generator potentials to discharges are particularly likely candidates.

Imperceptible electrical noise attenuates isometric plantar flexion force fluctuations with correlated reductions in postural sway

Optimal levels of noise stimulation have been shown to enhance the detection and transmission of neural signals thereby improving the performance of sensory and motor systems. The first series of experiments in the present study aimed to investigate whether subsensory electrical noise stimulation applied over the triceps surae (TS) in seated subjects decreases torque variability during a force-matching task of isometric plantar flexion and whether the same electrical noise stimulation decreases postural sway during quiet stance. Correlation tests were applied to investigate whether the noise-induced postural sway decrease is linearly predicted by the noise-induced torque variability decrease. A second series of experiments was conducted to investigate whether there are differences in torque variability between conditions in which the subsensory electrical noise is applied only to the TS, only to the tibialis anterior (TA) and to both TS and TA, during the force-matching task with seated subjects. Noise stimulation applied over the TS muscles caused a significant reduction in force variability during the maintained isometric force paradigm and also decreased postural oscillations during quiet stance. Moreover, there was a significant correlation between the reduction in force fluctuation and the decrease in postural sway with the electrical noise stimulation. This last result indicates that changes in plantar flexion force variability in response to a given subsensory random stimulation of the TS may provide an estimate of the variations in postural sway caused by the same subsensory stimulation of the TS. We suggest that the decreases in force variability and postural sway found here are due to stochastic resonance that causes an improved transmission of proprioceptive information. In the second series of experiments, the reduction in force variability found when noise was applied to the TA muscle alone did not reach statistical significance, suggesting that TS proprioception gives a better feedback to reduce force fluctuation in isometric plantar flexion conditions.

Models of passive and active dendrite motoneuron pools and their differences in muscle force control

Motoneuron (MN) dendrites may be changed from a passive to an active state by increasing the levels of spinal cord neuromodulators, which activate persistent inward currents (PICs). These exert a powerful influence on MN behavior and modify the motor control both in normal and pathological conditions. Motoneuronal PICs are believed to induce nonlinear phenomena such as the genesis of extra torque and torque hysteresis in response to percutaneous electrical stimulation or tendon vibration in humans. An existing large-scale neuromuscular simulator was expanded to include MN models that have a capability to change their dynamic behaviors depending on the neuromodulation level. The simulation results indicated that the variability (standard deviation) of a maintained force depended on the level of neuromodulatory activity. A force with lower variability was obtained when the motoneuronal network was under a strong influence of PICs, suggesting a functional role in postural and precision tasks. In an additional set of simulations when PICs were active in the dendrites of the MN models, the results successfully reproduced experimental results reported from humans. Extra torque was evoked by the self-sustained discharge of spinal MNs, whereas differences in recruitment and de-recruitment levels of the MNs were the main reason behind torque and electromyogram (EMG) hysteresis. Finally, simulations were also used to study the influence of inhibitory inputs on a MN pool that was under the effect of PICs. The results showed that inhibition was of great importance in the production of a phasic force, requiring a reduced co-contraction of agonist and antagonist muscles. These results show the richness of functionally relevant behaviors that can arise from a MN pool under the action of PICs.