M. Daskalova

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

Membrane property abnormalities in simulated cases of mild systematic and severe focal demyelinating neuropathies.

The investigation of multiple nerve membrane properties by mathematical models has become a new tool to study peripheral neuropathies. In demyelinating neuropathies, the membrane properties such as potentials (intracellular, extracellular, electrotonic) and indices of axonal excitability (strength-duration time constants, rheobases and recovery cycles) can now be measured at the peripheral nerves. This study provides numerical simulations of the membrane properties of human motor nerve fibre in cases of internodal, paranodal and simultaneously of paranodal internodal demyelinations, each of them mild systematic or severe focal. The computations use our previous multi-layered model of the fibre. The results show that the abnormally greater increase of the hyperpolarizing electrotonus, shorter strength-duration time constants and greater axonal superexcitability in the recovery cycles are the characteristic features of the mildly systematically demyelinated cases. The small decrease of the polarizing electrotonic responses in the demyelinated zone in turn leads to a compensatory small increase of these responses outside the demyelinated zone of all severely focally demyelinated cases. The paper summarizes the insights gained from these modeling studies on the membrane property abnormalities underlying the variation in clinical symptoms of demyelination in Charcot-Marie-Tooth disease type 1A, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome and multifocal motor neuropathy. The model used provides an objective study of the mechanisms of these diseases which up till now have not been sufficiently well understood, because quite different assumptions have been given in the literature for the interpretation of the membrane property abnormalities obtained in hereditary, chronic and acquired demyelinating neuropathies.

Differences in Membrane Properties in Simulated Cases of Demyelinating Neuropathies: Internodal Focal Demyelinations without 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.

Channels, currents and mechanisms of accommodative processes in simulated cases of systematic demyelinating neuropathies

To clarify the mechanisms of accommodative processes in systematic demyelinating neuropathies, this study presents the kinetics of the ionic, transaxonal and transmyelin currents defining the electrotonic potentials in different segments of human demyelinated motor fibres. The electrotonic potentials are obtained for fibres, which are in simulated cases of internodal, paranodal and simultaneously of paranodal internodal demyelinations, each of them systematic. The computations used our previous double-cable model of the fibre. The results show that the slow components of the electrotonic potentials depend on the activation of the channel types in the nodal or internodal axolemma, whereas the fast components of the potentials are determined mainly by the passive cable responses, i.e. by the capacitances and resistances of the corresponding different segments along the fibre. In the nodal segments, the depolarizing electrotonus is determined mainly by the activation of the K(+) slow nodal channels, whereas in the paranodal and internodal segments the potentials depend on the activation of the K(+) fast and slow internodal channels. For the hyperpolarizing electrotonus, the contribution of the activating inward rectifier (IR) and leak (Lk) channels in the internodal axolemma dominates in the total ionic currents. The results show that the greater polarizing electrotonic potentials and their defining currents in the mild systematic demyelinations abnormally increase when these demyelinations are severe. The study summarizes the insights gained from these modeling investigations of the accommodative mechanisms underlying the threshold electrotonus abnormalities observed in demyelinating neuropathies such as Charcot-Marie-Tooth type 1A and chronic inflammatory demyelinating polyneuropathy.

Differences between the channels, currents and mechanisms of conduction slowing/block and accommodative processes in simulated cases of focal demyelinating neuropathies

To clarify the differences between the mechanisms of conduction slowing/block and accommodative processes in focal demyelinating neuropathies, this computational study presents the kinetics of the ionic, transaxonal and transmyelin currents defining the intracellular and electrotonic potentials in different segments of human motor nerve fibres. The computations use our previous double cable model of the fibres. The simulated fibres have focal demyelination of internodes, paranodes or both together. The intracellular potentials are defined mainly by the Na+ current, as the contribution of the K+ fast and K+ slow currents to the total nodal ionic current is negligible. The paranodal demyelinations cause an increase in the transaxonal current and a decrease in the transmyelin current at the paranodal segments. However, there is an inverse relationship between the transaxonal and transmyelin currents at the same segments in the cases of internodal demyelination. The internodal ionic channels beneath the myelin sheath do not contribute to the intracellular potentials, but they show a high sensitivity to long-lasting pulses. The slow components of the electrotonic potentials depend on the activation of the channel types in the nodal or internodal axolemma, whereas the fast components of the potentials are determined mainly by the passive cable responses. However, the current kinetics changes (defining the investigated electrotonic changes) are relatively weak. The study summarizes the results from these modelling investigations on the mechanisms underlying the conduction slowing/block and accommodative processes in focal demyelinating neuropathies such as Guillain–Barré syndrome and multifocal motor neuropathy.

TEMPERATURE EFFECTS ON SIMULATED HUMAN NODAL ACTION POTENTIALS AND THEIR DEFINING CURRENT KINETICS

RESULTS: For all temperature dependent cases: (i) nodal, paranodal and mid-internodal action potentials are similar, with a small drop to minimal amplitude in the centre of the internode; (ii) transaxonal and transmyelin currents rapidly diminish in amplitude as the distance from the node increases reaching equal minimal values in the intermodal centre; (iii) the current kinetics of the paranodal and mid-internodal action potentials is slightly changed in the physiological range of 32-37C, and (iv) internodal ionic currents beneath the myelin sheath (I Na , I Kf , I Ks , I IR , and I Lk ) are not temperature-dependent.

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).

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.

Effects of Temperature on Adaptive Processes in Simulated Chronic Inflammatory Demyelinating Polyneuropathy at 20°C−42°C

The effects of temperature (from 20 o C to 42 o C) on action and polarizing electrotonic potentials (nodal and internodal) and their current kinetics were previously studied by us in a simulated case of 70% chronic inflammatory demyelinating polyneuropathy (70%CIDP). To complete the cycle of our studies on adaptive processes in this case, 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 myelinated human motor nerve fibre and the temperature is increased from 20 o C to 42 o C. The results show that as the action and polarizing electrotonic potential parameters, these excitability parameters are more sensitive to the hyperthermia (³ 40 o C) and are most sensitive to the hypothermia (£ 25 o C), especially at 20 o C, than at temperatures in the range of 28 o C−37 o C. With the increase of temperature from 20 o C to 42 o C, the strength-duration time constant decreases ~5.2 times, while it decreases ~3.5 times in the physiological range of 28 o C−37 o C. Conversely, the rheobasic current increases ~3.0 times from 20 o C to 42 o C, while it increases ~1.2 times in the range of 28 o C−37 o C. As in the normal case, the behavior of axonal superexcitability in the CIDP case is complex in a 100 ms recovery cycle with the increase of temperature. The axonal superexcitability decreases with the increase of temperature during hypothermia and increases with the increase of temperature during hyperthermia, especially at 42 o C. However, the superexcitability period in the CIDP case is followed by a late subexcitability period at 37 o C only and the recovery cycles are with reduced superexcitability and without relative refractory periods in the range of 20 o C−40 o C. The present results are essential for the interpretation of mechanisms of excitability parameter changes obtained here and measured in CIDP patients with symptoms of cooling, warming and fever, which can result from alterations in body temperature. They suggest that the adaptive processes in CIDP patients are in higher risk during hypothermia than during hyperthermia.