A modelling study to dissect the potential role of voltage-gated ion channels in activity-dependent conduction velocity changes as identified in small fiber neuropathy patients.

Objective: Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans.

Novel surface electrode design for preferential activation of cutaneous nociceptors.

Small area electrodes enable preferential activation of nociceptive fibers. It is debated, however, whether co-activation of large fibers still occurs for the existing electrode designs. Moreover, existing electrodes are limited to low stimulation intensities, for which behavioral and physiological responses may be considered less reliable.

Increased preferential activation of small cutaneous nerve fibers by optimization of electrode design parameters.

Electrical preferential activation of small nociceptive fibers may be achieved with the use of specialized small area electrodes, however, the existing electrodes are limited to low stimulation intensities. As existing electrodes have been developed empirically, the present study aimed to use computational modeling and optimization techniques to investigate if changes in electrode design parameters could improve the preferential activation of small fibers.Two finite element models; one of a planar concentric and one of an intra-epidermal electrode were combined with two multi-compartmental nerve fiber models of an Aδ-fiber and an Aβ-fiber.

Small and large cutaneous fibers display different excitability properties to slowly increasing ramp pulses.

The excitability of large nerve fibers is reduced when their membrane potential is slowly depolarizing, i.e., the fibers display accommodation.

Cold aggravates abnormal excitability of motor axons in oxaliplatin-treated patients.

Introduction: Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear.

Methods: Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures.

Results: Seven patients were eligible for examination.

Altered excitability of small cutaneous nerve fibers during cooling assessed with the perception threshold tracking technique.

Background: There is a need for new approaches to increase the knowledge of the membrane excitability of small nerve fibers both in healthy subjects, as well as during pathological conditions. Our research group has previously developed the perception threshold tracking technique to indirectly assess the membrane properties of peripheral small nerve fibers. In the current study, a new approach for studying membrane excitability by cooling small fibers, simultaneously with applying a slowly increasing electrical stimulation current, is evaluated.

From Perception Threshold to Ion Channels-A Computational Study.

Small-surface-area electrodes have successfully been used to preferentially activate cutaneous nociceptors, unlike conventional large area-electrodes, which preferentially activate large non-nociceptor fibers. Assessments of the strength-duration relationship, threshold electrotonus, and slowly increasing pulse forms have displayed different perception thresholds between large and small surface electrodes, which may indicate different excitability properties of the activated cutaneous nerves. In this study, the origin of the differences in perception thresholds between the two electrodes was investigated.

C-fiber recovery cycle supernormality depends on ion concentration and ion channel permeability.

Following each action potential, C-fiber nociceptors undergo cyclical changes in excitability, including a period of superexcitability, before recovering their basal excitability state. The increase in superexcitability during this recovery cycle depends upon their immediate firing history of the axon, but also determines the instantaneous firing frequency that encodes pain intensity. To explore the mechanistic underpinnings of the recovery cycle phenomenon a biophysical model of a C-fiber has been developed.

Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors.

Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers.

Dampening of hyperexcitability in CA1 pyramidal neurons by polyunsaturated fatty acids acting on voltage-gated ion channels.

A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet.

Integration of synchronous synaptic input in CA1 pyramidal neuron depends on spatial and temporal distributions of the input.

Highly synchronized neural firing has been discussed in relation to learning and memory, for instance sharp-wave activity in hippocampus. We were interested to study how a postsynaptic CA1 pyramidal neuron would integrate input of different levels of synchronicity. In previous work using computational modeling we studied how the integration depends on dendritic conductances.

Reversing nerve cell pathology by optimizing modulatory action on target ion channels.

In diseases of the brain, the distribution and properties of ion channels display deviations from healthy control subjects. We studied three cases of ion channel alteration related to epileptogenesis. The first case of ion channel alteration represents an enhanced sodium current, the second case addresses the downregulation of the transient potassium current K(A), and the third case relates to kinetic properties of K(A) in a patient with temporal lobe epilepsy.

Role of A-type potassium currents in excitability, network synchronicity, and epilepsy.

A range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A-type potassium current (K(A)). Epileptogenic activity comprises a rich repertoire of characteristics, one of which is synchronized activity of principal cells as revealed by occurrences of for instance fast ripples.