Some do not like it hot

Across the clinical neurosciences, it may be argued that the greatest physiological contributions have been derived in the realm of demyelinating disease. Following the landmark studies of Hodgkin & Huxley (1952), unlocking the mechanisms of neurotransmission, there dawned a therapeutic era across clinical neurology. That has been no more remarkable than in the field of central demyelination, multiple sclerosis in particular. From a position of no treatment option some 20 years ago, there are now more than 15 effective therapies available for patients struck down in the prime of life, with multiple sclerosis typically manifesting in female patients in their early twenties. In addition to the acute treatment of flares or exacerbations of their multiple sclerosis, significant disabilities are now also being avoided.

The chief role of human axons remains that of impulse transmission, in turn dependent on the electrical cable structure and voltage‐dependent ion channels of the axonal membrane (Fig. 1). While Ranvier established the existence of nodes in myelinated axons more than a hundred years ago, recent decades have witnessed a surge in understanding of the axonal membrane and its constituent ion channels. This understanding continues to evolve, as illustrated by the article by Kanagaratnem and colleagues (2017), published in this issue of The Journal of Physiology. Studying a rodent preparation of optic nerve, a structure typically involved in acute presentations of multiple sclerosis, the authors have explored a warming‐induced hyperpolarization (first reported by Coates et al. 2015), which may be explained by a temperature‐dependent electroneutral Na⁺ influx, countered by electrogenic Na⁺ pumping. In this issue of The Journal, the authors reported that raising the temperature reduced axonal excitability, increased the superexcitable period and tended to slow impulse conduction. In contrast, digital afferents in the human appeared much less sensitive to changing temperature, and thereby provided a further demonstration of a functional difference between the resting properties of central and peripheral axons, consistent with the effects of temperature in peripheral demyelination being less notable and requiring relatively large temperature swings (cf. Chaudhry et al. 1993).

Figure 1. Saltatory Conduction.

Neural transmission involving myelinated axons of the human nervous system occurs by means of saltatory conduction, with action potentials advancing between successive nodes of Ranvier. Normal saltatory conduction in myelinated axons is determined by the constituent ion channels distributed along the axonal membrane: Na⁺ channels (Na_t transient and Na_p persistent) are found in high concentrations at the node, as are slow K⁺ channels (K_s); fast potassium channels (K_f) are almost exclusively paranodal; while inward rectifier channels (I_h), permeable to both K⁺ and Na⁺ ions, act to limit axonal hyperpolarisation, whereas the Na⁺/K⁺ pump and leak (L_k) conductances serve to reverse ionic fluxes that may be generated through activity. In demyelinated axons, these processes become unstable, the safety margin becomes reduced and conduction failure develops because warming speeds the gating of channels, reducing the time integral of the Na⁺ current at each node of Ranvier. In demyelinated central axons, these processes become unstable, the safety factor is reduced and conduction failure develops not only because warming speeds channel gating, and reduces action currents, but, as proposed by Kanagaratnam et al., electroneutral Na⁺ entry is increased, hyperpolarizing the membrane potential.

It is now well understood that acute demyelination lowers the safety margin for impulse conduction, such that axons can become sensitive to shifts in membrane potential, even when those shifts occur through normal physiological mechanisms. In critically conducting axons, impulse conduction can be impaired by the effects of heat and probably by any mechanism that produces a significant shift in membrane potential, whether depolarizing or hyperpolarizing (Kiernan & Bostock, 2000).

Of relevance to such discussion, raising temperature by as little as half a degree Celsius can precipitate conduction failure in critically conducting axons (Uhthoff's phenomenon), and warming commonly accentuates the symptoms and neurological deficits in multiple sclerosis. Conduction failure develops because warming speeds the gating of channels, affecting both activation and inactivation, thereby decreasing the time integral of the Na⁺ current at the node of Ranvier. In a critically conducting axon, the duration of the driving current at the blocking node can reach a millisecond, with conduction block (CB) precipitated or relieved by manoeuvres that manipulate the time course of the driving current, such as changing temperature or the administration of agents that interfere with Na⁺ channel inactivation.

Activity can also hyperpolarize axons. With brief high‐frequency trains, this is largely due to activation of a nodal slow K⁺ conductance. When an axon conducts long impulse trains, particularly at a high frequency, there is an accumulation of Na⁺ ions within the axon, and this activates the Na⁺/K⁺ pump to restore ionic balance. Activity‐dependent hyperpolarization has been demonstrated in human sensory and human motor axons and, importantly, it can be produced by natural activity (Vagg et al. 1998). The extent and duration of the hyperpolarization depends on the discharge rate and train length. Importantly, voluntary contractions lasting as little as 15 s can increase the threshold of motor axons by 15%, with this effect lasting up to 10 min. Such changes are likely to be clinically relevant: a conservative estimate of the safety margin for impulse conduction in a series of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) suggested that significant conduction failure would occur if the axons hyperpolarized by approximately 14%. For the same impulse load, the extent of the activity‐dependent hyperpolarization seems to be greater for motor axons than for sensory axons (Kiernan et al. 2004). An important factor in this difference is probably the difference in the hyperpolarization‐activated cation conductance (Ih).

In patients with inflammatory demyelinating polyneuropathies, normal activity‐dependent hyperpolarization can precipitate conduction failure at sites of impaired function. This was first demonstrated in multifocal motor neuropathy and subsequently in CIDP. There is nothing special about activity: any process that produces sufficient hyperpolarization will produce clinically significant conduction block at pathological sites in these disorders, provided that a sufficient number of axons are critically conducting. The release of ischaemia results in a post‐ischaemic hyperpolarization, and this too can precipitate conduction failure.

Paradoxically, in CIDP, conduction failure may also occur during ischaemia during the depolarizing shift in membrane potential. This probably occurs because depolarization inactivates transient Na⁺ channels, thus decreasing the availability of functioning channels in an axon that is critically dependent on the size of the Na⁺ current. It is also possible that ischaemia produces an ischaemic metabolite that blocks Na⁺ channels, a mechanism that would further limit the number of Na⁺ channels available for the action current.

The study by Kanagaratnem and colleagues (2017) further emphasizes the important message that critically conducting axons are delicately poised. Conduction may fail if the membrane potential is too far from threshold or if the Na⁺ current becomes inadequate because of heating or because of a limitation on the number of functioning Na⁺ channels. Significant shifts in membrane potential may be sufficient to produce a transient worsening of symptoms. Clinical fluctuations are well documented in multiple sclerosis and in peripheral demyelinating polyneuropathies, and become more prominent if a sufficient number of axons can only just maintain conduction.

Additional information

Competing interests

None declared.

Funding

The author's work is funded by the Department of Health, Australian Government; and the National Health and Medical Research Council (NHMRC): 1037746.