SCS has been shown to be effective in treating an increasing array of neuropathic pain conditions, however nociceptive pain conditions remain largely recalcitrant to currently available SCS options. We hypothesized that a treatment that could directly inhibit neural function may enable effective relief for both neuropathic and nociceptive pain. While the neuromodulation field was built on the pioneering work of Hodgkin and Huxley detailing the mechanisms of how action potentials are initiated or inhibited, existing neurostimulation devices are designed only to directly activate neural tissue, using short duration pulses.

Spinal cord stimulation (SCS) is an electrical neuromodulation treatment for refractory chronic pain. Different SCS modalities produce analgesia in ostensibly different fashions by applying distinct temporal waveforms. Waveforms have been investigated not just to activate fibers, but to produce analgesia by inhibiting the conduction of action potentials. For example, direct current (DC) waveforms can inhibit action potential conduction along axons, but DC waveforms can lead to electrode and/or tissue damage. However, recent innovations have enabled the delivery of “DC-like” waveforms at an ultra-low frequency (ULFTM). This ULFTM waveform consists of two plateau phases of constant current with opposite polarity, connected by crossover phases, that repeat with a period of several seconds. This ULFTM waveform has shown promise in both preclinical and clinical work. Therefore, in this study, we used an anatomically realistic model of lower thoracic SCS to compare the physiological effects of the ULFTM waveform to a DC waveform.

The ability of direct current (DC) to interrupt transmission along nerves and the potential application of this effect for analgesia has been known for many years. However, passing direct current into neural tissue via traditional materials causes tissue damage. Materials science innovations have enabled new protocols to deliver 'DC-like' waveforms at an ultra-low frequency (ULFTM). The ULFTM waveform has shown promise in both pre-clinical studies and initial clinical work. Here, we present data that demonstrate the modulating effect of ULFTM on sensory fibre conduction.

Purpose: The purpose of this trial was to evaluate the safety and efficacy of OC-01 (varenicline solution), a nicotinic acetylcholine receptor agonist nasal spray, on signs and symptoms of dry eye disease. Methods: A phase 2b, multicenter, randomized, double-masked, vehicle-controlled trial (ONSET-1; NCT03636061) was performed. Patients were aged 22 years or older with a physician's diagnosis of dry eye disease and previous use of artificial tears were randomized 1:1:1:1 to control (vehicle nasal spray twice daily [BID]), OC-01 0.006 mg BID, OC-01 0.03 mg BID, and OC-01 0.06 mg BID. The primary end point was the change in the anesthetized Schirmer test score from baseline to day 28 in the study eye. The secondary end points included the change in the eye dryness score from baseline to day 28. Results: One hundred eighty-two patients were randomized. After 28 days, patients who received OC-01 0.03 or 0.06 mg showed a statistically significant improvement in tear film production relative to vehicle, with least squares mean differences from vehicle of 7.7 mm [95% confidence interval, 3.8-11.7; P < 0.001] with OC-01 0.03 mg and 7.5 mm (95% confidence interval, 3.4-11.6; P < 0.001) with OC-01 0.06 mg. Patients receiving OC-01 0.03 mg showed a significant reduction in the eye dryness score by day 28 versus vehicle (P = 0.021); those receiving the OC-01 0.06 mg dose showed a nonsignificant reduction versus vehicle. OC-01 administration was associated with sneezing (62%-84%) and cough (9%-25%); these were transient and predominantly mild in severity. Conclusions: OC-01 nasal spray administered BID at 0.03 and 0.06 mg resulted in significant improvements in signs and symptoms of dry eye disease, was well tolerated, and warrants further clinical investigation.

Chronic pain remains a leading cause of disability worldwide, and there is still a clinical reliance on opioids despite the medical side effects associated with their use and societal impacts associated with their abuse. An alternative approach is the use of electrical neuromodulation to produce analgesia. Direct current can block action potential propagation but leads to tissue damage if maintained. We have developed a form of ultra low frequency (ULF) biphasic current and studied its effects. In anesthetized rats, this waveform produced a rapidly developing and completely reversible conduction block in >85% of spinal sensory nerve fibers excited by peripheral stimulation. Sustained ULF currents at lower amplitudes led to a slower onset but reversible conduction block. Similar changes were seen in an animal model of neuropathic pain, where ULF waveforms blocked sensory neuron ectopic activity, known to be an important driver of clinical neuropathic pain. Using a computational model, we showed that prolonged ULF currents could induce accumulation of extracellular potassium, accounting for the slowly developing block observed in rats. Last, we tested the analgesic effects of epidural ULF currents in 20 subjects with chronic leg and back pain. Pain ratings improved by 90% after 2 weeks. One week after explanting the electrodes, pain ratings reverted to 72% of pretreatment screening value. We conclude that epidural spinal ULF neuromodulation represents a promising therapy for treating chronic pain.

High frequency alternating current (HFAC) waveforms reversibly block conduction in mammalian peripheral nerves. The initiation of the HFAC produces an onset response in the nerve before complete block occurs. An amplitude ramp, starting from zero amplitude, is ineffective in eliminating this onset response. In fact, it makes the onset worse. We postulated that initiating the ramp from a non-zero amplitude would produce a different effect on the onset. This was tested in an in-vivo rat sciatic nerve model. HFAC was applied at supra block threshold amplitudes and then reduced to a lower amplitude (0%, 25% 50 %, 75% and 90% of the suprathreshold amplitude). The amplitude was then increased again to the original supra block threshold amplitude. This normally produces a second period of onset response if increased as a step. However, an amplitude ramp was successful in eliminating this onset. This was always possible for the ramps up from 50%, 75 % and 90% block threshold amplitude, but never from 0% or 25% of the block threshold amplitude. This maneuver can potentially be used to maintain complete nerve block, transition to partial block and then resume complete block without initiating another onset.

Background: Kilohertz frequency alternating currents (KHFAC) produce rapid nerve conduction block of mammalian peripheral nerves and have potential clinical applications in reducing nerve hyperactivity. However, there are no experimental measurements of the block inception time (BIT) for the complete block of mammalian motor axons, i.e. the time from the start of delivery of the KHFAC to the axons reaching a fully blocked state. New method: A "counted cycles" method (CCM) was designed to exploit characteristics of the onset response, which is typical of KHFAC block, to measure the BIT with a millisecond time resolution. Randomized and repeated experiments were conducted in an in-vivo rodent model, using trains of KHFAC over a range of complete cycle counts at three frequencies (10, 20, and 40 kHz). Results: Complete motor nerve conduction block was obtained in the rat sciatic nerve (N = 4) with an average BIT range of 5 ms-10 ms. The fastest BIT measured was 2.5 ms-5 ms. There was no statistical difference between the block inception times for the three frequencies tested. Comparison with existing methods: There are no comparable methods to measure the KHFAC BIT. Conclusion: The KHFAC BIT is faster than previously estimated. KHFAC motor nerve block is established in milliseconds. These results may assist in the design of methods to eliminate the onset response produced by KHFAC nerve block.

Dry eye, a multifactorial disease of the tears and ocular surface, leads to tear film instability, potentially resulting in tear film hyperosmolarity, ocular surface epithelial damage, and inflammation. Impaired visual-related function associated with dry eye disease poses a significant economic and humanistic burden worldwide. Current treatment options are mostly palliative in nature, intended to supplement tears and alleviate dry eye symptoms. Neuromodulation is an established therapeutic strategy utilizing the direct activation of neural pathways to correct organ dysfunction and manage disease symptoms. A novel intranasal tear neurostimulation device has been developed, designed to increase tear production and improve tear quality in patients with dry eye by activating the nasolacrimal neuronal pathway through electrical stimulation of sensory nerve endings in the nasal mucosa. In clinical studies, the intranasal tear neurostimulator has demonstrated ability to increase tear production and improve symptoms, showing promise as a treatment option for patients with dry eye.