Restoration of somatosensory function by pairing vagus nerve stimulation with tactile rehabilitation
Darrow MJ, Mian TM, Torres M, Haider Z, Danaphongse T, Rennaker RL 2nd, Kilgard MP, Hays SA
What is this paper about?
This paper investigates if pairing VNS with tactile rehabilitation can improve sensory function after peripheral nerve injury (PNI). Simply put, this PNI model causes the rat’s paw to be less sensitive (it takes much more force for the animal to respond to a touch stimulus on their injured paw) and by pairing VNS with tactile rehab, we saw a significant improvement in sensory function as their sensory thresholds just about returned to normal.
What got you interested in this topic?
This became of large interest to me after Dr. Kilgard ran a case study on improving sensory function on a Stroke patient who had made great motor improvements after the phase 1 VNS Stroke Motor trial, but still had debilitating sensory deficits (the patients couldn’t feel touch that was less than 250 grams of force, aka someone poking you hard). This patient made huge improvements in sensory function, but this was only a case study. There were no controls and we didn’t know if this effect was real or what caused it. So I wanted to test this in a preclinical setting in the lab to see if we could better understand this effect, and if we could possibly improve on it to better treat future patients.
Why is this paper important? How does it advance the field?
This paper is very important as it is the first evidence that VNS can be utilized to improve your ability to feel, following neurological injury. This brings about a whole new region of possibility for the treatment of sensory dysfunction that is caused by a multitude of neurological injuries and may provide some insight on how we may be able to treat chronic pain in the future. Although this is a very exciting finding, there is still lots of work to do to better understand this effect and to improve it towards better sensory discrimination in patients. I look forward to the future preclinical and clinical trials that will take place on this topic over the next few years.
What are the real-world implications of this paper?
This treatment could mean huge advancements for patients with sensory loss in the near future. Not being able to feel something causes major difficulties with everyday life, and I think this new treatment could really make a difference in peoples’ lives. This work has led to the construction of multiple types of sensory rehabilition to be included in the future clinical trials for VNS, and I cannot wait to see the results!
How did you divide up all the work?
This was a brand new rehabilitation that we created as I built a brand new set of cages, systems, and program to implement VNS paired with tactile input, but for this study I really had a lot of help! My students, Tabarak Mian, Miranda Torres, Zainab Haider and Tanya Danaphongse really contributed a lot with the PNI and VNS surgeries, the 6 different behavioral assessments (occurring multiple times a week), immunohistochemistry of the injured nerves, animal health care, and daily tactile rehabilitation. These few students did the bulk of the work with a team of 15 or so other students who mainly helped with daily tactile rehabilitation and some health care of the animals.
What was the most surprising result in the paper?
There were few surprising results in this paper. First was that mechanosensory withdrawal thresholds returned back to normal, and then persisted for 9 weeks after VNS treatment and tactile rehabilitation. This was very encouraging as we provide evidence that the effect is long-lasting after the treatment suggesting that the changes to the neural circuitry are permanent. Also the large effect seen in improvements in locomotion were a bit of a shock to me. I would have guessed that pairing VNS with motor rehab would provide a large benefit to locomotion, but we provide strong evidence that by greatly improving sensory function, the toe spread and ladder walking ability had significant improvements. This really illustrates how important the sensory system is for locomotion in general.
Were there any interesting setbacks along the way? How did you handle it?
I had the idea of testing the footprint of these animals, and my first thought was to use some of the newer technologies utilizing video software to measure footprints during treadmill walking of an animal. I attempted to do this before the study began, but I ran into some technical difficulties. Dr. Kilgard and Hays suggested to try and go “old school” by using non-toxic ink and just have the animals walk down a corridor on some paper. This method took some trouble shooting as well, but we eventually figured out a very consistent method to measure the footprints of animals during normal walking. In the end, I am very happy we did the assessment this way and actually have some very funny art with rat footprints on paper everywhere in the lab.