Inspired by Sokal et al 2021.
IF – impact factorkey to acronyms
VNS – vagal nerve stimulation
SpNS – splenic nerve stimulation
NVB – neurovascular bundle
SpN – splenic nerve
SpA – splenic artery
SpV – splenic vein
IPG – implanted pulse generator
eCAP – evoked compound action potential
LPS – lipopolysaccharide (usually derived from E coli)
mABP – mean arterial blood pressure
SPMs – specialised pro-resolutive lipid mediators
EA – electroacupuncture
I guess this was an inevitable progression of what has come to be known as ‘bioelectric medicine’. I was drawn to this paper to see how far development had progressed in our attempts to hack our own neuroimmune feedback mechanisms. This paper was published in the open access journal Frontiers in Immunology (IF 7.561).
I have been increasingly frustrated by the lack of clinical research on acupuncture as a cheap and safe means of indirect activation of the vagal anti-inflammatory reflex. See the blog from 13th March for a review of indirect VNS.
This series of experiments in direct splenic nerve stimulation (SpNS) was performed on pigs apparently because their physiology and immune functions more closely resemble those of humans than the more usual rodent models. It was also convenient of course that the neurovascular bundle (NVB) of the SpN, SpA & SpV is a considerably larger target in a 74–99kg pig, and the physical size of the IPG device is unlikely to be noticed in such a large animal.
The first experiment was to determine the best stimulation settings for the SpN, bearing in mind that it is mostly composed of unmyelinated fibres and that the nerve fascicles are distributed in the fatty tissue around the SpA. As a result of a number of experiments and observation they found the best approach was to use 10Hz stimulation in 0.5 second bursts at a burst frequency of 1Hz. The parameters being juggled were maintenance of efficient evoked compound action potentials (eCAPs) from more distal on the SpN, plus minimal effects on SpA blood flow and systemic mean arterial blood pressure (mABP).
Having established the best stimulation parameters, implanted pigs were challenged with LPS–induced endotoxaemia, and demonstrated anti-inflammatory effects in a variety of parameters including TNF–α and certain monocyte levels.
In addition to reducing pro-inflammatory responses, SpNS led to the peripheral accumulation of specialised pro-resolutive lipid mediators (SPMs), which are able to influence leucocyte responses.
Importantly there was no systemic immune suppression prior to LPS administration, unlike the problem with some biologics.
On the whole this is good reductionist medicine, but it leaves me wishing they had included a group with peripheral indirect VNS (such as EA) for comparison.
1 Sokal DM, McSloy A, Donegà M, et al. Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs. Front Immunol 2021;12:649786. doi:10.3389/fimmu.2021.649786
2 Peeples L. Core Concept: The rise of bioelectric medicine sparks interest among researchers, patients, and industry. Proc Natl Acad Sci U S A 2019;116:24379–82. doi:10.1073/pnas.1919040116