Temperature effects on accommodative processes in simulated amyotrophic lateral sclerosis in the physiological range.

The present study investigates the temperature dependence of electrotonic potentials in mathematically-simulated myelinated axons with one of three increasingly-severe type of amyotrophic lateral sclerosis (ALS) pathology, termed as ALS1, ALS2 and ALS3, respectively, in the physiological range (30-37∘C). These potentials were elicited by long-lasting (100 ms) subthreshold polarizing current stimuli (±40% of the threshold). Numerical solutions were computed using our temperature-dependent multi-layered model. The results showed the following trends: (i) in ALS1, polarizing electrotonic potentials were normal; (ii) in ALS2 and ALS3, action potentials were elicited in the early parts of the depolarizing electrotonic potentials, and (iii) in ALS3, spontaneous discharges were elicited after the termination of applied hyperpolarizing stimuli (i.e., post-anodal excitation). The ionic currents underlying electrotonic potentials in the ALS1 case were attributable to the activation of potassium fast (Kf+) and slow (Ks+) channels in the nodal and internodal axolemma beneath the myelin sheath. By contrast, in ALS2 and ALS3, the depolarizing stimuli activated the classical "transient" Na+ channels in the nodal and internodal axolemma beneath the myelin sheath eliciting action potential generation. These results obtained were closer to those observed in hypothermia (⩽25∘C) than in hyperthermia (⩾40∘C).

Theoretical predication of temperature effect on conducting processes in simulated amyotrophic lateral sclerosis at 20-40[Formula: see text]C.

The present study investigates action potential abnormalities in previously simulated cases of amyotrophic lateral sclerosis, termed as ALS1, ALS2 and ALS3, respectively, when the temperature is changed from 20[Formula: see text]C to 42[Formula: see text]C. These ALS cases are modeled as three progressively severe axonal abnormalities. The effects of temperature on the kinetics of currents, defining action potentials in the normal and abnormal cases, are also given and discussed. These computations use our temperature-dependent multi-layered model of human motor nerve fibers. The results show that the classical "transient" sodium current ([Formula: see text]) contributes mainly to the nodal action potential generation in the normal and abnormal cases for the temperature range of 20-39[Formula: see text]C, as the contribution of fast and slow potassium currents ([Formula: see text] and [Formula: see text]) to the total ionic current ([Formula: see text]) is negligible. However, the contribution of [Formula: see text] and [Formula: see text] to the membrane repolarization is enhanced at temperatures higher than 39[Formula: see text]C, especially at 42[Formula: see text]C, and the after-potentials are hyperpolarized in the normal and ALS1 cases, while, they are re-depolarized in the ALS2 and ALS3 cases. The ionic channels beneath the myelin sheath are insensitive to the short-lasting current stimuli and do not contribute to the internodal action potential generation for the normal and abnormal cases in the whole investigated temperature range. Nevertheless that the uniform axonal dysfunction progressively increases in the nodal and internodal segments of each next simulated ALS case, the action potentials cannot be regarded as definitive indicators for the progressive degrees of this disease, when the temperature is changed from 20[Formula: see text]C to 42[Formula: see text]C. However, the results are essential for the interpretation of mechanisms of action potential measurements in ALS patients with symptoms of cooling, warming and fever, which can result from alteration in body temperature. Our results also suggest that the conducting processes in patients with ALS are in higher risk during hyperthermia ([Formula: see text]C) than hypothermia ([Formula: see text]C).

Theoretical predication of temperature effects on accommodative processes in simulated amyotrophic lateral sclerosis during hypothermia and hyperthermia.

Electrotonic potentials allow the accommodative processes to long-lasting subthreshold polarizing stimuli to be assessed. The present study investigates such potentials in previously simulated cases of amyotrophic lateral sclerosis, termed as ALS1, ALS2 and ALS3, respectively, when the temperature is changed during hypothermia ([Formula: see text]C) and hyperthermia ([Formula: see text]C). The ALS cases are modeled as three progressively severe uniform axonal dysfunctions along the human motor nerve fiber which is simulated by our temperature-dependent multi-layered numerical model. The results show that the polarizing electrotonic potentials in the ALS1 case are quite similar to those in the normal case during hypothermia. Their defining currents are caused by the activation of potassium fast (K[Formula: see text]) and slow (K[Formula: see text]) channels in the nodal and internodal axolemma beneath the myelin sheath. Except in the ALS3 case at 20[Formula: see text]C, where the accommodative processes are blocked by depolarizing stimuli, in the ALS2 and ALS3 cases during hypothermia these stimuli activate the classical "transient" Na[Formula: see text] channels in the nodal and internodal axolemma beneath the myelin sheath. And this leads to action potential generations during the early parts of electrotonic responses in all compartments along the fiber length. Only in the ALS3 case after the termination of long-lasting subthreshold hyperpolarizing stimuli, action potential generations are obtained in the late parts of electrotonic potentials along the fiber length. In comparison to the normal case, in the gradually severe ALS cases, the depolarizing electrotonic potentials gradually increase, while the hyperpolarizing electrotonic potentials gradually decrease during hyperthermia. However, the repetitive firings are not obtained in these polarizing electrotonic potentials. The results show that the accommodative processes to depolarizing stimuli in the ALS3 case are more likely to be blocked during hypothermia than hyperthermia. The results also show that the polarizing electrotonic potentials in the three simulated ALS cases are specific indicators for the motor nerve disease ALS during hypothermia and hyperthermia.

Electrotonic potentials in simulated chronic inflammatory demyelinating polyneuropathy at 20°C-42°C.

Threshold electrotonus changes have been studied following warming to 37°C and cooling to 25°C in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To extend the tracking of these changes also during hypothermia (≤ 25°C) and hyperthermia (≥ 40°C), and to explain their mechanisms, we investigate the effects of temperature (from 20°C to 42°C) on polarizing nodal and internodal electrotonic potentials and their current kinetics in previously simulated case of 70% CIDP. The computations use our temperature-dependent multi-layered model of the myelinated human motor nerve fiber. While the changes of electrotonic potentials and their current kinetics are largely similar for the physiological range of 28-37°C, they are altered during hypothermia and hyperthermia in the normal and CIDP cases. The normal (at 37°C) resting membrane potential is further depolarized or hyperpolarized during hypothermia or hyperthermia, respectively, and the internodal current types defining these changes are the same for both cases. Unexpectedly, our results show that in the CIDP case, the lowest and highest critical temperatures for blocking of electrotonic potentials are 20°C and 39°C, while in the normal case the highest critical temperature for blocking of these potentials is 42°C. In the temperature range of 20-39°C, the relevant potentials in the CIDP case, except for the lesser value (at 39°C) in hyperpolarized resting membrane potential, are modified: (i) polarizing nodal and depolarizing internodal electrotonic potentials and their defining currents are increased in magnitude; (ii) inward rectifier (I IR ) and leakage (I Lk ) currents, defining the hyperpolarizing internodal electrotonic potential, are gradually increased with the rise of temperature from 20°C to 39°C, and (iii) the accommodation to long-lasting hyperpolarization is greater than to depolarization. The present results suggest that the electrotonic potentials in patients with CIDP are in high risk for blocking not only during hypothermia and hyperthermia, but they are also in risk for worsening at the temperature range of 37-39°C.

Conducting processes in simulated chronic inflammatory demyelinating polyneuropathy at 20°C-42°C.

Decreased conducting processes leading usually to conduction block and increased weakness of limbs during cold (cold paresis) or warmth (heat paresis) have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To explore the mechanisms of these symptoms, the effects of temperature (from 20°C to 42°C) on nodal action potentials and their current kinetics in previously simulated case of 70% CIDP are investigated, using our temperature dependent multi-layered model of the myelinated human motor nerve fiber. The results show that potential amplitudes have a bifid form at 20°C. As in the normal case, for the CIDP case, the nodal action potentials are determined mainly by the nodal sodium currents (I Na ) for the temperature range of 20-39°C, as the contribution of nodal fast and slow potassium currents (I Kf and I Ks ) to the total ionic current (Ii) is negligible. Also, the contribution of I Kf and I Ks to the membrane repolarization is enhanced at temperatures higher than 39°C. However, in the temperature range of 20-42°C, all potential parameters in the CIDP case, except for the conduction block during hyperthermia (≥ 40°C) which is again at 45°C, worsen: (i) conduction velocities and potential amplitudes are decreased; (ii) afterpotentials and threshold stimulus currents for the potential generation are increased; (iii) the current kinetics of action potentials is slowed and (iv) the conduction block during hypothermia (≤ 25°C) is at temperatures lower than 20°C. These potential parameters are more altered during hyperthermia and are most altered during hypothermia. The present results suggest that the conducting processes in patients with CIDP are in higher risk during hypothermia than hyperthermia.

Effects of temperature on simulated electrotonic potentials and their current kinetics of human motor axons at 20°C-42°C.

To expand our studies on accommodation in human motor nerve axons, the effects of temperature on polarizing nodal and internodal electrotonic potentials and their current kinetics are investigated. The computations use our temperature dependent multi-layered model of the myelinated human motor nerve fiber and the temperature is increased from 20°C to 42°C. The results show that for temperatures from 28°C to 37°C, the polarizing electrotonic potentials almost coincide, as the kinetics of their ionic currents is changed a little. The normal (at 37°C) resting membrane potential is further depolarized or hyperpolarized during hypothermia (≤ 25°C) or hyperthermia (≥ 40°C), respectively and its change is determined by the flow of ionic currents through the internodal axolemma during the polarizing current stimuli. The polarizing electrotonic potentials are more altered during hypothermia and are most altered during hyperthermia. During hyperthermia, the depolarizing nodal and internodal electrotonic potentials are determined by the nodal slow (I Ks ) and internodal fast (I Kf ) and slow (I Ks ) potassium currents. The hyperpolarizing internodal electrotonic potentials are determined by the activation of internodal channels, which are different during hyperthermia at 40°C and 42°C. These potentials are determined by the internodal I Ks current at 40°C and by the internodal inward rectifier (I IR ) and leakage (I Lk ) currents at 42°C. The difference in accommodation to hyperpolarizing currents during focal and uniform hyperthermia at 42°C is discussed. The present results are essential for the interpretation of mechanisms of threshold electrotonus measurements in subjects with symptoms of cooling, warming and fever, which can result from alterations in body temperature.

Theoretical predications of the effects of temperature on simulated adaptive processes in human motor nerve axons at 20°C-42°C.

The effects of temperature on conducting and accommodative processes in the myelinated human motor nerve fiber were previously studied by us in the range of 20°C-42°C. To complete the cycle of our studies on adaptive processes in the fiber, the temperature effects on strength-duration time constant, rheobasic current and recovery cycle are investigated. The computations use our temperature dependent multi-layered model of the fiber and the temperature is increased from 20°C to 42°C. The results show that these excitability parameters are more sensitive to the hypothermia (≤ 25°C) and are most sensitive to the hyperthermia (≥ 40°C), especially at 42°C, than at temperatures in the range of 28°C-37°C. With the increase of temperature from 20°C to 42°C, the strength-duration time constant decreases ~ 8.8 times, while it decreases ~ 2.7% per °C in the range of 28°C-37°C. Conversely, the rheobasic current increases ~ 4.4 times from 20°C to 42°C, while it increases ~ 2.3% per °C in the range of 28°C-37°C. The behavior of relative refractory period and axonal superexcitability in a 100 ms recovery cycle is complex with the increase of temperature. The axonal superexcitability decreases with the increase of temperature during hypothermia. However, it increases rapidly with the increase of temperature during hyperthermia, especially at 42°C and a block of each applied third testing stimulus is obtained. The superexcitability period is followed by a late subexcitability period when the temperatures are in the physiological range of 32°C-37°C. The present results are essential for the interpretation of mechanisms of excitability parameter changes obtained here and measured in healthy subjects with symptoms of cooling, warming and fever, which can result from alterations in body temperature. Our present and previous results confirm that 42°C is the highest critical temperature for healthy subjects.

Mechanisms defining the action potential abnormalities in simulated amyotrophic lateral sclerosis.

The present study investigates action potential abnormalities obtained in simulated cases of three progressively greater degrees of uniform axonal dysfunctions. The kinetics of the currents, defining the action potential propagation through the human motor nerve in the normal and abnormal cases, are also given and discussed. These computations use our previous multi-layered model of the myelinated motor axon, without taking into account the aqueous layers within the myelin sheath. The results show that the classical "transient" Na(+) current contributes mainly to the action potential generation in the nodal segments, as the contribution of the nodal fast and slow potassium currents to the total nodal ionic current is negligible. However, the ionic channels beneath the myelin sheath are insensitive to the short-lasting current stimuli and do not contribute to action potential generation in the internodal compartments along the fibre length. The slight changes obtained in the currents underlying the generated action potentials in the three amylotropic lateral sclerosis cases are consistent with the effect of uniform axonal dysfunction along the fibre length. Nevertheless that the uniform axonal dysfunction progressively increases in the nodal and internodal segments of each next simulated amylotropic lateral sclerosis case, the action potentials cannot be regarded as definitive indicators for the progressive degrees of this disease.

Mechanisms defining the electrotonic potential abnormalities in simulated amyotrophic lateral sclerosis.

Electrotonic potentials allow the accommodative processes to polarizing stimuli to be assessed. Electrotonic potential transients in response to applied polarizing stimuli are caused by the kinetics of underlying axonal conductances. Here, we study these transients using our multi-layered model of the human motor nerve, in three simulated cases of the motor neuron disease amyotrophic lateral sclerosis (ALS): ALS1, ALS2 and ALS3 are three consecutively greater degrees of uniform axonal dysfunctions along the human motor nerve fibre. The results show that the responses in the ALS1 case are quite similar to the normal case. In contrast, in the ALS2 and ALS3 cases, long-lasting (100 ms) subthreshold depolarizing stimuli activate the classical "transient" Na(+) channels in the nodal and in the internodal axolemma beneath the myelin sheath; this leads to action potential generation during the early parts of the electrotonic responses in all compartments along the fibre length. The results also show that the electrotonic potentials in response to long-lasting (100 ms) subthreshold hyperpolarizing stimuli in the ALS1 and ALS2 cases are quiet similar to those of the normal case. However, the current kinetics in the ALS3 case differs from the normal case after the termination of the long-lasting hyperpolarizing stimuli. In the most abnormal ALS3 case, the activation of the Na(+) channels in the nodal and in the internodal axolemma leads to repetitive action potential generation in the late parts (100-200 ms) of the hyperpolarizing electrotonic responses. The results show that the repetitive firing, due to the progressively increased nodal and internodal ion channel dysfunction, are consistent with the loss of functional potassium channels involving both the fast and the slow potassium channel types. The results confirm that the electrotonic potentials in the three simulated ALS cases are specific indicators for the motor neuron disease ALS. The mechanisms underlying the simulated ALS are also discussed.

The aqueous layers within the myelin sheath modulate the membrane properties of simulated hereditary demyelinating neuropathies.

To expand our studies on the mechanisms underlying the clinical decline of the nerve excitability properties in patients with hereditary demyelinating neuropathies, the contribution of myelin sheath aqueous layers on multiple membrane properties of simulated fiber demyelinations is investigated. Three progressively greater degrees of internodal systematic demyelinations (two mild and one severe termed as ISD1, ISD2 and ISD3, respectively) without/with aqueous layers are simulated using our previous multi-layered model of human motor nerve fiber. The calculated multiple membrane excitability properties are as follows: potentials (intracellular action, electrotonic), strength-duration time constants, rheobasic currents and recovery cycles. They reflect the propagating, accommodative and adaptive processes in the fibers. The results show that all membrane properties, except for the strength-duration time constants and refractoriness, worsen when the myelin lamellae and their corresponding aqueous layers are uniformly reduced along the fiber length. The effect of the aqueous layers is significantly higher on the accommodative and adaptive processes than on the propagating processes in the fibers. Our multi-layered model better approximated some of the functional deficits documented for axons of patients with Charcot-Marie-Tooth disease type 1A. The study provides new and important information on the mechanisms underlying the pathophysiology of hereditary demyelinating neuropathies.

The myelin sheath aqueous layers improve the membrane properties of simulated chronic demyelinating neuropathies.

Recently, patients with chronic demyelinating neuropathies have demonstrated significant abnormalities in their multiple nerve excitability properties measured by a non-invasive threshold tracking technique. In order to expand our studies on the possible mechanisms underlying these abnormalities, which are not yet well understood, we investigate the contributions of the aqueous layers within the myelin sheath on multiple membrane properties of simulated fibre demyelinations. Four degrees of systematic paranodal demyelinations (two mild demyelinations termed PSD1 and PSD2, without/with aqueous layers respectively, and two severe demyelinations termed PSD3 and PSD4, with/without aqueous layers, respectively) are simulated using our previous multi-layered model of human motor nerve fibre. We studied the following parameters of myelinated axonal function: potentials (intracellular action, electrotonic-reflecting the propagating and accommodative fibre processes, respectively) and strength-duration time constants, rheobases, recovery cycles (reflecting the adaptive fibre processes). The results show that each excitability parameter is markedly potentiated when the aqueous layers within their paranodally demyelinated sheaths are taken into account. The effect of the aqueous layers is significantly higher on the propagating processes than on the accommodative and adaptive processes in the fibres. The aqueous layers restore the action potential propagation, which is initially blocked when they are not taken into account. The study provides new and important information on the mechanisms of chronic demyelinating neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP).

Simulating focal demyelinating neuropathies: membrane property abnormalities.

Membrane properties such as potentials (intracellular, extracellular, electrotonic) and axonal excitability indices (strength-duration and charge-duration curves, strength-duration time constants, rheobasic currents, recovery cycles) can now be measured in healthy subjects and patients with demyelinating neuropathies. They are regarded here in two cases of simultaneously reduced paranodal seal resistance and myelin lamellae in one to three consecutive internodes of human motor nerve fiber. The investigations are performed for 70 and 96% myelin reduction values. The first value is not sufficient to develop a conduction block, but the second leads to a block and the corresponding demyelinations are regarded as mild and severe. For both the mild and severe demyelinations, the paranodally internodally focally demyelinated cases (termed as PIFD1, PIFD2, and PIFD3, respectively, with one, two, and three demyelinated internodes) are simulated using our previous double-cable model of the fiber. The axon model consists of 30 nodes and 29 internodes. The membrane property abnormalities obtained can be observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN). The study confirms that focal demyelinations are specific indicators for acquired demyelinating neuropathies. Moreover, the following changes have been calculated in our previous papers: (1) uniform reduction of myelin thickness in all internodes (Stephanova et al. in Clin Neurophysiol 116: 1153-1158, 2005); (2) demyelination of all paranodal regions (Stephanova and Daskalova in Clin Neurophysiol 116: 1159-1166, 2005a); (3) simultaneous reduction of myelin thickness and paranodal demyelination in all internodes (Stephanova and Daskalova in Clin Neurophysiol 116: 2334-2341, 2005b); and (4) reduction of myelin thickness of up to three internodes (Stephanova et al., in J Biol Phys, 2006a,b, DOI: 10.1007/s10867-005-9001-9; DOI: 10.1007/s10867-006-9008-x). The membrane property abnormalities obtained in the homogeneously demyelinated cases are quite different and abnormally greater than those in the case investigated here of simultaneous reduction in myelin thickness and paranodal demyelination of up to three internodes. Our previous and present results show that unless focal demyelination is severe enough to cause outright conduction block, changes are so slight as to be essentially indistinguishable from normal values. Consequently, the excitability-based approaches that have shown strong potential as diagnostic tools in systematically demyelinated conditions may not be useful in detecting mild focal demyelinations, independently of whether they are internodal, paranodal, or paranodal internodal.

Simulating mild systematic and focal demyelinating neuropathies: membrane property abnormalities.

This study provides numerical simulations of some of the abnormalities in the potentials and axonal excitability indices of human motor nerve fibers in simulated cases of internodal, paranodal and simultaneously of paranodal internodal demyelinations, each of them systematic or focal. A 70% reduction of the myelin lamellae (defining internodal demyelination), or of the paranodal seal resistance (defining paranodal demyelination), or simultaneously both of them (defining paranodal internodal demyelination) was uniform along the fiber length for the systematically demyelinated subtypes. These permutations were termed internodal systematic demyelination (ISD), paranodal systematic demyelination (PSD) and paranodal internodal systematic demyelination (PISD). In other tests, the same reductions of the myelin sheath parameters were used but restricted to only three (8th, 9th and 10th) consecutive internodes. Such fiber demyelinations were termed internodal focal demyelination (IFD), paranodal focal demyelination (PFD) and paranodal internodal focal demyelination (PIFD). The computations used our previous double cable model of the fibers. The axon model was comprised of 30 nodes and 29 internodes. The 70% reduction value was not sufficient to develop conduction block in all investigated demyelinations, which were regarded as mild. The membrane property abnormalities obtained in the ISD, PSD and PISD cases were quite different and abnormally greater than those in the IFD, PFD and PIFD cases. The changes in the excitability indices such as strength-duration time constants, rheobasic currents and recovery cycles in the focally demyelinated subtypes were so slight as to be essentially indistinguishable from normal values. Consequently, the excitability based approaches that have shown strong potential as diagnostic tools in systematically demyelinated conditions may not be useful in detecting mild focal demyelinations. The membrane property changes simulated in the systematically demyelinated subtypes are in good accordance with the data from patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP). The excitability abnormalities obtained in each focally demyelinated subtype match those observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome (GBS). The results indicate that the model that was used is a rather promising tool in studying the membrane property abnormalities of hereditary, chronic and acquired demyelinating neuropathies, which up till now, have not been sufficiently well understood.

Differences in membrane properties in simulated cases of demyelinating neuropathies: internodal focal demyelinations without conduction block.

The membrane properties (intracellular, extracellular, electrotonic potentials, strength-duration time constants, rheobasic currents and recovery cycles), which can now be measured in healthy subjects and patients with demyelinating neuropathies, are investigated in simulated cases of focal reduction (70%) of the myelin sheath in one, two and three successive internodal segments along the length of human motor fibres. The internodally focally demyelinated cases (termed as IFD1, IFD2 and IFD3, respectively) are simulated using our previous double cable model of the fibres. The results show that the intracellular potentials are with reduced amplitude and slowed conduction velocity in the vicinity of demyelinated segments, however the segmental conduction block is not achieved. The radial decline of the extracellular potential amplitudes slightly increases with the increase of the radial distance and demyelination. In contrast, the electrotonic potentials, strength-duration time constants and rheobases are normal. In the recovery cycles, the refractoriness, supernormality and less late subnormality are close to the normal, showing that the pathology is relatively minor. The obtained abnormalities in the potentials and excitability properties provide new information about the pathophysiology of the demyelinated human motor axons and can be observed in vivo in patients with acquired demyelinating neuropathies.

Differences in membrane properties in simulated cases of demyelinating neuropathies: internodal focal demyelinations with conduction block.

The aim of this study is to investigate the membrane properties (potentials and axonal excitability indices) in the case of myelin wrap reduction (96%) in one, two and three consecutive internodes along the length of human motor nerve fibre. The internodally focally demyelinated cases (termed as IFD1, IFD2 and IFD3, respectively, with one, two and three demyelinated internodes are simulated using our previous double cable model of the fibre. The progressively greater increase of focal loss of myelin lamellae blocks the invasion of the intracellular potentials into the demyelinated zones. For all investigated cases, the radial decline of the extracellular potential amplitudes increases with the increase of the radial distance and demyelination, whereas the electrotonic potentials show a decrease in the slow part of the depolarizing and hyperpolarizing responses. The time constants are shorter and the rheobases higher for the IFD2 and IFD3 cases than for the normal case. In the recovery cycles, the same cases have less refractoriness, greater supernormality and less late subnormality than the normal case. The simulated membrane abnormalities can be observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome. The study provides new information about the pathophysiology of acquired demyelinating neuropathies.

Differences in potentials and excitability properties in simulated cases of demyelinating neuropathies. Part III. Paranodal internodal demyelination.

OBJECTIVE: The aim of this study is to investigate the potentials (intracellular, extracellular, electrotonic) and excitability properties (strength-duration and charge-duration curves, strength-duration time constants, rheobasic currents, recovery cycles) in progressively greater degrees of uniform reduction (20, 50 and 70%) of the paranodal seal resistance and myelin lamellae along the fibre length. METHODS: Three paranodally internodally systematically demyelinated cases (termed as PISD1, PISD2 and PISD3, respectively) are simulated using our previous double cable model of human motor nerve fibres. RESULTS: The results conform that in the more severely demyelinated cases, the intracellular potentials are with significantly reduced amplitude, prolonged duration and slowed conduction velocity, whereas the electrotonic potentials show abnormally greater increase in the early part of the hyperpolarizing responses. The extracellular potentials indicate increased polyphasia in the PISD3 case. The strength-duration time constants are shorter and the rheobasic currents higher in the demyelinated cases. In the recovery cycles, the demyelinated cases have less refractoriness, greater supernormality and less late subnormality than the normal case. CONCLUSIONS: The uniform reduction of the paranodal seal resistance and myelin thickness along the fibre length has significant effects on the potentials and excitability properties of the simulated demyelinated human motor fibres. Unexpectedly, the PISD fibres behave like paranodally demyelinated ones, since the myelin reduction increases slightly the effect of the paranodal demyelination on the nerve membrane properties. The study shows that the excitability properties in demyelinating neuropathies are much more largely determined by the paranodal changes than by the internodal changes. SIGNIFICANCE: The study provides new and important information about the pathophysiology of human demyelinating neuropathies.

Differences in potentials and excitability properties in simulated cases of demyelinating neuropathies. Part I.

OBJECTIVE: The aim of this study is to investigate the potentials (intracellular, extracellular, electrotonic) and excitability properties (strength-duration and charge-duration curves, strength-duration time constants, rheobases, recovery cycles) in three cases of uniform myelin wrap reduction (20, 50 and 70%) along the fibre length. METHODS: The internodally systematically demyelinated cases (termed as ISD1, ISD2 and ISD3) are simulated using our previous double cable model of human motor fibres. RESULTS: In the more severely demyelinated cases, the intracellular potentials are with significantly reduced amplitude, prolonged duration and slowed conduction velocity, whereas the electrotonic potentials show greater increase in the early part of the hyperpolarizing responses. The radial decline of the extracellular potential amplitudes depends on the radial distance of the field point and increases with the increase of the distance and demyelination. The time constants and rheobasic currents increase with the increase of the degree of demyelination. In the recovery cycles, the more severely demyelinated cases have greater refractoriness (the increase in threshold current during the relative refractory period), supernormality and less late subnormality than the normal case. CONCLUSIONS: The myelin thickness has significant effects on the potentials and axonal excitability properties of the simulated demyelinated human motor fibres. The obtained abnormalities in the potentials and excitability properties can be observed in Charcot-Marie-Tooth disease type 1A (CMT1A). SIGNIFICANCE: The study provides new information about the pathophysiology of human demyelinating neuropathies.

Differences in potentials and excitability properties in simulated cases of demyelinating neuropathies. Part II. Paranodal demyelination.

OBJECTIVE: The purpose of the present investigation is to study the potentials and axonal excitability properties in progressively greater degrees of uniform paranodal demyelination of human motor nerve fibres. METHODS: Using our previous double cable model of human motor nerve fibre, 3 paranodally systematically demyelinated cases (termed as PSD1, PSD2 and PSD3) are simulated by an uniform paranodal resistance reduction (20, 50 and 77%) along the fibre length. RESULTS: Considerably reduced amplitudes, prolonged durations and slowed conduction velocities are obtained for the intracellular potentials of the PSD2 and PSD3 cases. In contrast, the electrotonic potentials show abnormally greater increase in the early part of the hyperpolarizing responses. The extracellular potentials indicate increased polyphasia in the PSD3 case. The strength-duration time constants are shorter and the rheobases higher in the demyelinated cases. In the recovery cycles, the demyelinated cases have less refractoriness, greater supernormality and less late subnormality than the normal case. CONCLUSIONS: The reduction of the paranodal seal resistance has significant effects on the potentials and axonal excitability properties of the simulated demyelinated human motor fibres. The obtained abnormalities in the potentials and excitability properties can be observed in vivo in patients with chronic inflammatory demyelinating polyneuropathy. SIGNIFICANCE: The study provides important information about the pathology of human demyelinating neuropathies.

Excitability properties of normal and demyelinated human motor nerve axons.

The strength-duration time constants and rheobase currents, which provide an indirect indication of the axonal properties are calculated in two cases of stimulation, using our previous double cable models of normal and demyelinated human motor fibres. The time constants and rheobases are defined as nodal when the case of point fibre polarization (intracellular current application at the first node) is used for their calculations, whereas the time constants and rheobases are defined as internodal when the case of periodic kind of uniform fibre polarization (simultaneous intracellular current application at each axon segment) is used. Four fibre demyelinations (termed as paranodal focal 1 systematic and internodalfocal 1 systematic demyelinations) are studied. For both investigating cases of current application, the stimulus duration is increased in 0.025-ms steps from 0.025-ms to 1-ms and the strength-duration and charge-duration curves are plotted for the axons. The strength-duration time constants are calculatedfrom the curve-fitting equation for the resulting charge-duration curves. The results are consistent with the interpretation that the time constants depend not only on the types of the demyelinated axon, but on the methods of fibre stimulation. The strength-duration time constants (nodal 1 internodal) are almost the same for the normal axons and focally demyelinated axons, however, they are shorter for the paranodally systematically demyelinated axons, and longer for the internodally systematically demyelinated axons. For all investigated cases, the internodal time constants are greater than the nodal time constants and there is an inverse relationship between the time constants and rheobase currents.

Extracellular potentials of myelinated and demyelinated human motor nerve fibres.

The extracellular potentials of myelinated and demyelinated human motor nerve fibres in an unbounded volume conductor are studied. Using our previous double-cable models of normal and demyelinated human fibres, the spatial and temporal intracellular potentials are calculated in the cases of point polarization and adaptation of the fibres. The intracellular potentials are then used as input to a line source model that allows to calculate the corresponding spatial and temporal extracellular potentials at various radial distances in the surrounding volume conductor. Four fibre demyelinations (termed as internodal focal\systematic and paranodal focal\systematic demyelinations, respectively) are studied. In all investigated cases, the radial decline of the peak-to-peak amplitude of the extracellular potential depends on the radial distance of the field point and increases with the increase of the distance. The results are consistent with the interpretation that the considerably different spatial and temporal distributions of the extracellular potentials depend not only on the cable properties of the fibres, but on the methods of fibre stimulation. In the case of fibre adaptation, the temporal extracellular potentials in the normal and demyelinated cases correspond well with electromyograms (EMGs) from healthy subjects and patients with demyelinated disorders as reported in the literature. Simulation results indicate that the models used are rather promising tools in studying the main properties of compound action potentials in patients with demyelinated disorders which up till now have not been sufficiently well understood.