Potential Preventive Strategies for Amyotrophic Lateral Sclerosis.

It may seem useless to propose preventive measures for a disease without established pathogenesis and successful therapy, such as amyotrophic lateral sclerosis (ALS). However, we will show that ALS shares essential molecular mechanisms with aging and that established anti-aging strategies, such as healthy diet or individually adjusted exercise, may be successfully applied to ameliorate the condition of ALS patients. These strategies might be applied for prevention if persons at ALS risk could be identified early enough. Recent research advances indicate that this may happen soon.

Age-related change in duration of afterhyperpolarization of human motoneurones.

Motor unit (MU) potentials were recorded from brachial biceps of healthy subjects aged 5.5-79 years. The subjects were subdivided into young (5.5-19 year) and adult (37.5-79 year) groups, between which single MU discharge characteristics were compared. Firing rates were in the ranges of 8.3-21.7 s(-1) (mean 12.87 s(-1)) and 5.9-18.7 s(-1) (mean 11.08 s(-1)) for young and adult groups, respectively. Standard deviations (s.d.) of interspike intervals (ISIs) were in the range 4.84-11.57 ms (mean 8.39 ms) for the young group and 4.26-12.23 ms (mean 7.76 ms) for the adult group. Both differences were statistically significant (P < 0.001). Special attention was paid to the previously developed method of ISI variability analysis, which enabled the comparison of MUs with respect to afterhyperpolarization (AHP) duration of their motoneurones (MNs). The results show that AHP duration increases gradually with increasing age, which is in line with the transformation of muscle properties towards a slower phenotype. This transformation seems to be a continuous process, covering the entire lifespan of a human being, from childhood to senescence. The results presented here are significant for their insight into the ageing process of the neuromuscular system. The age-related change in AHP duration has not been investigated previously in human studies and has been met with ambiguous results in animal studies.

Evaluation of methods for assessment of interneuronal interaction.

Analysis of motor unit (MU) activity gives an insight to relationships between physiologically activated human motoneurons (MNs). It was assumed that the investigation of recurrent inhibition under these conditions might advance our understanding of the role it plays in motor control. To allow for proper interpretation of experimental results, a series of computer simulations modeling different interactions between MNs was performed. For analysis, several modifications of crosscorrelation technique were applied. These functions complement each other and help to decide about the character of the interaction. The results show that with the same IPSP parameters, inhibition is more pronounced when the firing rate of the target MN is lower. Even IPSP of the amplitude as low as 0.05 mV has characteristic effects on all the functions applied in this study. If the effect is present only on one function, it is certainly an artifact.

Are motoneurons involved in muscular dystrophy?

In the early seventies, a suggestion that even in muscular dystrophy a neurogenic factor may be involved, was formulated. The argument which followed this suggestion, resulted in eventual abandoning of this concept even by its author. This discussion however has never been supported by any systematic study of motoneuron activity in muscular dystrophy. We examined an activity of motoneurons supplying brachial biceps in eight controls and 26 patients affected by Duchenne muscular dystrophy by studying single motor unit (MU) potentials picked up by fine wire bipolar electrodes. In the majority of patients, MU firing rates were higher as compared to controls and increased more rapidly with increasing force level. The relationship between standard deviation of interspike intervals and their mean value, SD(x), was shifted towards the shorter intervals and lower SDs. The numerical values describing these changes were correlated with severity of the disease. There is evidence that the break-point of the function SD(x) is correlated with motoneuron properties, in particular with after-hyperpolarization duration. In muscular dystrophy, this break-point corresponds to the shorter interspike intervals. We suggest that the motoneurons in muscular dystrophy are altered either in response to the muscle degeneration, or as a result of the disease itself.

Motoneurons are altered in muscular dystrophy.

The activity of motoneurons supplying the brachial biceps muscle was examined in eight control subjects and 26 patients affected by Duchenne muscular dystrophy. The patients were subdivided into two groups: one whose motor units (MU) fired with normal rates (N group) and the other whose MU firing rates were higher as compared to controls (I group). Firing rates of motoneurons of patients from group I increased more rapidly with increasing force level. The relationship between the standard deviation of interspike intervals and their mean value, sigma(Tm), was shifted towards the shorter intervals and lower standard deviations in both groups of patients. The numerical values describing these changes correlated with the severity of disease. The MU recruitment was comparable for control subjects and for patients. Experimental results as well as computer simulations indicate that the break-point of the function sigma(Tm) is correlated with motoneuronal properties, and in particular with the afterhyperpolarization (AHP) duration. In muscular dystrophy this break-point corresponds to the shorter interspike intervals. Therefore, we propose that the motoneurons in muscular dystrophy are altered either in response to the muscle degeneration or as a result of the disease itself.

An influence of afterhyperpolarization on the pattern of motoneuronal rhythmic activity.

Motoneuronal spike trains were generated according to a simple model assuming algebraical summation of the afterhyperpolarization (AHP) curve and noisy synaptic inflow. An influence of various model parameters on the relationship between standard deviation (SD), sigma, of interspike intervals (ISIs) and their mean value, Tm, was studied. A typical sigma(Tm) relationship resembled those obtained experimentally and consisted of two parts: a short-interval part with constant sigma and a long-interval part where sigma increased linearly with increasing ISI. It is concluded that the placement of the range of transition between short- and long-interval parts of the plot depends on the properties of the motoneuron and not on those of the synaptic inflow. The break-point interval of the plot is correlated with the AHP duration but is shorter than it. Further, not only are the curves for shorter AHP durations shifted towards shorter ISIs, but they also have lower SDs at their short-interval parts.

MU firing characteristics in human dystrophic muscle.

During isometric contractions of constant force surface EMG as well as intramuscular MU potentials from extensor digitorum communis and biceps brachii muscles were recorded on magnetic tape for further off-line analysis. Surface EMG power spectra were computed and transformed so as to reveal low-frequency peaks which might correspond to MU firing rates. From intramuscular recordings, single MU action potentials were identified with an aid of semi-automatic recognition program. For each single MU action potential train (MUAPT) statistical parameter of interspike intervals (ISIs) were determined and related to the measured muscle force level. Sixty four MUAPTs from 9 patients and 55 MUAPTs from 4 normals were analysed so far. The estimates of MU firing rate from surface and needle EMG corresponded well to each other. The MU firing rates were higher in muscular dystrophy and this difference was more pronounced for higher levels of muscle force. The tendency towards mean MU firing rate increase is stronger for the patients with more advanced disease. The typical dependency of standard deviation of ISIs on their mean value may be approximated by two lines of different slope. There were reported experimental data indicating that the breaking point of this dependency may be an estimate of AHP duration in motoneurones. Our results for dystrophic muscle showed a shift of this point towards shorter ISIs, as compared to normals. This suggests that in muscular dystrophy also motoneurones may be altered, either by the disease itself or as a compensation for changes in muscular part of a MU.

Excitability of single firing human motoneurones to single and repetitive stimulation (experiment and model).

The activity of single motoneurones of m. flexor carpi ulnaris (FCU) was investigated by recording their motor unit (MU) action potentials during weak and moderate voluntary muscle contractions. The MU firing rate range was 4.5-15 imp/s. The excitability of motoneurones was tested with a number of single stimuli eliciting a monosynaptic H-reflex of low amplitude. Two different indices were defined which relate to motoneuronal excitability: the response index--the ratio of the number of responses of a motoneurone to the total number of stimuli, and the response time--the time after the last background MU discharge at which motoneurone is ready to respond to the excitatory volley. Both the response index and the response time were determined for single motoneurones at different levels of background activity. In the lower range of firing rates, the response index for all motoneurones decreased when increasing the firing rate, but it remained constant in the higher rate range. This kind of response seems to be a typical motoneuronal response to the stimulation with single stimuli. The data on the response time were used to study the excitability of the same single motoneurones to computer simulated repetitive stimulation (stimulation rate 40-100 imp/s). In this case, the excitability of each motoneurone was determined as an increment of its firing rate in response to the stimulation. For the lower firing rate range, the excitability for all motoneurones also decreased when the firing rates increased whereas a variety of slopes was obtained in the higher rate range.(ABSTRACT TRUNCATED AT 250 WORDS)

[The action of a short inhibitory volley on human firing motoneurons (an experiment and a model)]. / Deistvie korotkoi tormoziashchei posylki na impul'siruiushchie motoneirony cheloveka (éksperiment i model').

The influence of a short inhibitory volley on firing motoneurons of soleus and ext. carpi uln. was studied in human experiments and the results obtained were used as a basis for simulation. An increase of the interspike interval (ISI) depended on the timing of inhibitory volley arrival and silent period (SP) duration was studied. The ability of the individual motoneuron to respond to inhibitory volley by prolongation of ISI influenced the SP duration. Two parameters were crucial: the duration of the part of ISI where the inhibition was efficient in increasing the ISI (d) and the maximal increase of ISI (delta x max). The latter corresponded to the inhibitory volley arrival at the very end of ISI. If d less than delta x max the SP = d; if d greater than delta x max the SP = delta x max. In the case of variable ISIs those relations should be applied to the smallest ISI among the ISI distribution. Therefore the SP duration depended not only on the mean ISI of a motoneuron, but on ISI variability as well.

Computer simulation study of the shape of motor unit action potential.

Motor unit action potentials (MUAPs) of brachial biceps were simulated. A simulated MUAP was obtained as a sum of single fibre action potentials (SFAPs) from all the muscle fibres of a motor unit (MU). The influence of the following factors on MUAP shape for different kinds of recording electrode was studied: fibre density, neuromuscular jitter, temporal dispersion and electrode displacements. The simulation confirms that typical MUAPs recorded with needle electrodes from muscles of low fibre density such as brachial biceps are usually triphasic. Increased fibre density produces MUAPs of more complex shape and higher amplitude. Normal neuromuscular jitter is responsible for the variability of shape of subsequent potentials from the same MU as well as for electromyographic shimmer. Pathologic (increased) jitter makes the shapes of subsequent potentials unrecognizable. The influence of temporal dispersion is interconnected with other factors but rather of minor importance. The simulation shows how big changes in MUAP shape can be expected due to electrode displacements during single experiment or during estimation of MU territory.

A method of description of single muscle fibre action potential by an analytical function V(t, r).

The paper describes a new method of analytical description of single muscle fibre action potential suitable for computer simulation. The description introduced is a product of quadratic and gaussian functions. The coefficients of the function are determined on the basis of dependences of SFAP parameters on electrode-to-fibre distance combined from the transformed results of electrophysiological experiments and modelling. The description is being used for computer simulation of motor unit action potential which results will be described in forthcoming papers.