By Tyler Shewbert
Abstract
The idea of electrical stimulation to treat medical disorders has been around since 1889. The first major device that was implemented successfully on a large scale was the pacemaker. It the past twenty years, there has been increased interest in the use of electrical stimulation of specific nerves as a method of treating various conditions. As the understanding of the way electrical pathways in the body effect the body’s function increase, researchers are able to explore new methods of treating common problems using electroceutical devices that are much less invasive than their predecessors such as deep brain stimulation and pacemakers. Vagus Nerve Stimulation (VNS) has been shown to be one of the most promising methods, allowing researchers to treat migraines, epilepsy, traumatic brain injury (TBI), inflammation, and other problems in humans and animals.
Introduction
Electroceuticals essentially work by manipulating the action potentials within the body which are responsible for controlling the body’s functions [1]. These actions potentials control the body’s functions through certain patterns which electroceutical devices are able to manipulated [1]. The main advantage of using electroceuticals rather than deep brain stimulation is that electroceuticals allow for the pinpointing of certain nerves while deep brain stimulations can influence large areas of nerves which are not related to treating the disease [1]. The recent developments in mapping the nervous system’s responsibilities in certain diseases such as obesity is enabling researchers to believe that electroceuticals can be an effective way of treating such diseases [1].
Electroceuticals are gaining interest from corporations and research institutions. In recent years, GlaxoSmithKline (GSK) and the National Institutes of Health have begun funding research initiatives backed by grants reaching into the hundreds of millions of dollars. The reward for companies such GSK and ElectroCore, which makes gammaCore, is that the regulatory framework for medical devices is much less costly and quicker than drug regulations. This will enable products to get to market quicker than their pharmacological based counterparts.
The vagus nerve plays a central role in the automatic nervous system which is responsible for the function of organs [2]. It is the longest nerve in the automatic nervous system [2]. Due to its important role in automatic nerve processes, it was hypothesized that electrically stimulating parts of the vagus nerve would be successful in treating a range of diseases [2]. Controlled stimulation of the vagus nerve has been used to treat epilepsy and was first performed in the 1990s [3]. This was traditionally performed by implanting a device on the vagus nerve in the neck and connecting it to a stimulator device implanted in the chest [4]. The gammaCore device has been shown to be successful in treating cluster headaches in human patients. Rheumatoid arthritis patients’ inflammation has been treated using VNS [3]. It was shown in rats and rabbits to have an effect in reducing the damage caused by traumatic brain injury [3]. Professor Chris Toumazou of Imperial College has developed a device that would help control hunger in patients suffering from obesity [2]. The actual clinical success of using VNS in treating humans is mixed [5]. However, due to its role in the nervous system, treating conditions with VNS is a tempting and worthwhile pursuit for researchers. In this paper, research on the stimulation of the vagus nerve as a treatment for cluster headaches, inflammation and traumatic brain injury will be surveyed.
Results and Discussion
The gammaCore device works by using an electroceutical device that is externally placed on the neck. The Prevention and Acute Treatment of Chronic Cluster Headache (PREVA) trial was performed on 45 patients using the gammaCore device and 47 who were not [4]. After four weeks, the group who have been routinely using the gammaCore device were suffering six less cluster headache attacks a week [4]. This is three times greater than the control group which was only suffering two less cluster headaches a week using traditional methods of treatment [4].
Another study was performed to see if the gammaCore device would work during an acute cluster headache attack. This trial was also successful, and 47% of the patients reported the attack was over within eleven minutes [4]. There was no control group to compare this to, but a study which tested pharmaceutical methods of treating acute cluster headache attacks found that it took two hours to be free of pain in only 22% of the cases [4]. This shows that electroceutical methods have the potential for being better at treating cluster headaches.
Kevin Tracy and his research team performed a proof-of-concept experiment to see whether or not VNS could be used successfully in treating inflammation in rheumatoid arthritis (RA) patients [4]. A VNS device was implanted within the chest of patients and stimulation was conducted for 42 days. After 42 days, the device was switched off for 14 days, and then turned on for another 28 days [4]. The Disease Activity Score (DAS), a method for tracking the activity of RA in patients, decreased for the first 42 days while the device was on, and then increased for the 14 days that the device was off, and then once again decreased for the last 28 days [4]. This shows that the VNS device was successful in reducing the inflammation caused by RA [4]. The timeline for the whole process is shown in the following figure:
Figure 1. Timeline for the RA study (from [6])
On Day 0 the patient received a 60 s stimulation of 250 ms pulses of a current of between 0.25-2.5 mA and then nothing again till Day 7 [6]. From Day 7 to Day 28, the current was set to a maximum tolerable value up to 2.0 mA and the 60 s stimulation of 250 ms pulses was used daily [6]. From Day 28 to Day 42, for patients who had not responded to the treatment, the stimulations were increased to four times a day [6].
The device inhibited the tumor necrosis factor successfully during the days which the device was turned on [6]. This was the component that was critical in reducing the inflammation in these patients. This study was small in scale, composed of only 17 patients, so large-scale studies are needed to see how effective this method of treatment is for reducing RA inflammation [6].
Studying the effects of VNS to treat traumatic brain injury on humans is much harder than the previous two studies mentioned here. This is because some sort of brain trauma has to occur. Studies on rats and rabbits have shown promising results [6]. Studies took the form of having the animal perform a cognitive test such as running a maze, traumatically injuring the brain, and the using VNS treatments for two to four weeks. In these studies, the use of VNS was successful in helping the animals perform the tasks that they had been taught before the injury after the trauma was experienced [6]. However, performing this type of study on humans is unethical, and it is also would be hard to perform studies on patients who had experienced TBI in the previous two hours, the time in which researchers believe that VNS needs to begin after the initial injury to the brain successfully treat it [6].
Outlook and relevance of work
Vagus Nerve Stimulation has to potential to treat a wide range of diseases and injuries. The power lies in the central role that the vagus nerve plays in the automatic nervous system. The three examples in this paper are only a few of the treatments being explored using VNS. Other studies have shown that it may be successful in treating obesity, which until now has required invasive surgery to treat. If we are able to continue to improve our knowledge of neural circuitry and how neural signal influence bodily functions, the ability to treat a large number of problems will be available. The funding in this field, several hundred million dollars, is still limited compared the billions of dollars spent of drug research each year. However, as the promise VNS and other types of electroceuticals is proven, it can be assumed that the funding will increase, enabling researchers to improve understanding how the electroceuticals are working. A major breakthrough, which would be a daunting undertaking, would be the full mapping of neural circuitry and signaling for several different problems. Once this is accomplished, a better understanding of the role that electroceuticals are playing in the alleviation of symptoms, and use that fundamental understanding to develop new treatments.
References
[1] K. Famm, B. Litt, K. J. Tracey, E. S. Boyden, and M. Slaoui, “Drug discovery: a jump-start for electroceuticals,” Nature, vol. 496, no. 7444, p. 159, 2013.
[2] G. Finnegan. (2016) Could tweaking a nerve beat obesity? Horizon.
[3] S. Miller and M. S. Matharu, “The Use of Electroceuticals and Neuromodulation in the Treatment of Migraine and Other Headaches,” in Electroceuticals: Advances in Electrostimulation Therapies, A. Majid, Ed. Cham: Springer International Publishing, 2017, pp. 1-33.
[4] A. Majid, Electroceuticals: Advances in Electrostimulation Therapies. Springer, 2017.
[5] S. K. Moore, “Follow the wandering nerve,” IEEE Spectrum, vol. 52, no. 6, pp. 78-82, 2015.
[6] F. A. Koopman et al., “Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis,” Proceedings of the National Academy of Sciences, vol. 113, no. 29, pp. 8284-8289, July 19, 2016 2016.