Upgrade Your Medicine: The Technical Details and Theoretical Background of Bioelectric Medicine
Doctors have been zapping people with electricity for thousands of years. It’s a somewhat classic paradigm of medicine: “We’re not sure exactly how or why this works, but it seems to be effective; let’s give it a shot!”
Some of the earliest accounts of “electro-therapy” date from the first century CE. Scribonius Largus, physician to the Roman Emperor Claudius, prescribed that a sufferer of gout (leg pain) should place an electric ray under his feet, while standing on moist ground, until the foot and lower leg are numb. A contemporaneous prescription noted by the Roman historian Galen was to cure intractable headaches by holding a live black electric ray to the spot in pain, until it is numb. The final application, which implies an early intuitive awareness of the relationship between electric stimulation and muscle tension, was the use of black electric ray to treat anal prolapse.
In the following centuries, the understanding of human of anatomy and physiology began to flourish. Electricity and physiology were formally connected in 1889, when the English doctor John Mac William described the application of electricity to rhythmic contraction in a weakened or stopped heart. This theoretical accomplishment was seen in the real world with the first definitive use of an implantable electronic pacemaker in 1958.
Pacemakers control the speed and rhythm of a heartbeat by applying electric stimulation at a certain rate. This technology makes use of Dr. William’s discovery that the heart is controlled by electricity naturally.
The heart is a fist-sized muscle composed of four chambers: the right atrium, left atrium, right ventricle, and left ventricle. Within the right ventricle is a cluster of muscle cells called the Sinoatrial Node (“SA” in the diagram below). This cluster has the shocking ability to provide electric stimuli to the heart, regulating heart rate to approximately 100 beats per minute (“bpm”) as a default. There is also an elegant network of nerves (“vagus nerve” and “sympathetic ganglia chain” below) and cellular signals (ACh and NE below) which act on the sinoatrial node to further influence the heart rate in response to activity, stress, and other behavioral factors.
Given how complex this regulatory network is, it is easy to understand that occasionally signals are crossed. While the reasons can vary from genetic predisposition and diet to physical activity and emotional health, interruptions and communication breakdowns occur at both the nerve and chemical level. This is where pacemaker technology shines.
Pacemakers are composed of a generating element (battery, pulse generator, controller) which creates the charge and a conducting element (wire leads and electrodes) which carries the charge to the heart. In modern pacemakers, the controller can monitor physiological conditions such as blood oxygen and blood pressure and adjust the supplied power and frequency in response. The conducting elements travel from the generating element (implanted within the chest cavity) and provide electric stimulation directly to the heart tissue. Just like Wile E. Coyote’s hand holding a power line, the heart muscle contracts when the stimulation is applied.
All in all, pacemaker theory is incredibly cool while also relatively simple: the heart is a muscle, when muscles are electrically stimulated they contract, and pacemakers provide electrical stimulation at an optimal power and rate. Keep this paradigm in mind as we dig into the newest application of electricity as a therapy: bioelectric regulation of the inflammatory reflex.
The inflammatory reflex is a nerve-mediated component of the body’s overall immune response. The immune response is the cellular version of a surveillance camera and security patrol.
A foreign object (“invader”) enters the body
Certain signalling cells in the immune system recognize an invader and identify it as such, turning on an alarm for the rest of the immune system
Other cells in the immune system respond to the alarm and attack the identified invader.
This response results in inflammation until the invader is destroyed (think of the redness, swelling, and heat that characterizes a bruise or laceration)
Once the threat is gone, the signalling cells turn off the alarm, the responding cells leave, and the inflammation subsides
Similar to the electric regulation of the heart, the immune response is vulnerable to dysfunction if there is miscommunication in the identification of invaders or in the response to them. There is a range of disorders known as “autoimmune disease” in which the immune system identifies itself or other self cells as invaders and begins to attack them (Lupus, dermatitis, multiple sclerosis, and Crohn’s disease are all examples of autoimmune diseases).
One of the critical cells in the immune system is called TNF-alpha, which is a signalling protein that recruits other immune cells to attack an invader. Because of its critical role, reducing TNF-alpha has long been studied as a way to minimize inflammation. This is what Kevin Tracey was studying in 2002 when he discovered the inflammatory reflex.
Tracey was studying the effect of TNF-alpha inhibition by injecting an experimental inhibitory drug into the bloodstream of lab rats near the site of inflammation. In one experiment, he injected the drug directly into the rats’ brains rather than in the bloodstream. This resulted in a reduction of TNF-alpha at the site of inflammation almost 100,000 times more potent than when the inhibitor had been injected directly into the bloodstream - instead of simply reducing it in the brain as expected. Tracey further observed that the inhibitory effect went away when the vagus nerve, which the brain uses to control a host of involuntary functions, was severed. Tracey and his colleagues have since elucidated the precise electrical, cellular and chemical pathways involved in the inflammatory reflex.
Therapies targeting the inflammatory response are currently under development, and at a high level the approach follows that of the pacemaker: organs are controlled by nerves, nerves are controlled by electricity, and if you can figure out how to stimulate them appropriately you can use electrical implants to control physiologic responses.This fundamental approach has application all across medicine, thanks to the inflammation theory of disease: namely, that inflammation is intimately linked to both infectious and non-infectious disease. There is a growing belief that electric regulation of the inflammatory response will prove to be an elegant and safe way to treat a host of medical conditions.
The next installment of Upgrade Your Medicine will explore the companies who working to make this belief a reality.
References:
The Part Played by Electric Fish in the Early History of Bioelectricty and Electrotherapy
Autonomic and endocrine control of cardiovascular function
Boston Scientific - How Pacemakers Work
The vagus nerve and the inflammatory reflex—linking immunity and metabolism