Neuromodulation Holds Promise for Treatment of Non-Neurological and Neurological Conditions


The history of neuromodulation and outlook for the future were topics addressed by Elliot Krames, MD, Past President, International Neuromodulation Society. Dr. Krames is Founding Editor of Neuromodulation: Technology at the Neural Interface, and now is Emeritus Editor-in-Chief. Dr. Krames’ presentation was the John D. Loeser, MD Lecture, at the 83rd Annual Scientific Meeting of the American Association of Neurological Surgeons in Washington, DC.
Man with electrodes placed on his back for transcutaneous electrical nerve stimulation or TENSNeuromodulatory medicine can be expected to exert an incalculable impact on medicine in the 21st century. Photo Source:

Historical Explorations

Neuromodulation owes its beginnings to Michael Faraday (1791-1867), whose research allowed electric current to be applied in a controlled fashion to the human body; a process that became known as Faradization. In 1855, Guillaume Duchenne (1806-1875) announced that alternating current was superior to direct current to trigger electrotherapeutic contractions.

The first modern device was the artificial pacemaker, which, in the 1930s, delivered ventricular stimuli and revived 14 of the 42 animals that the inventor, Albert S. Hyman, tested it on. In the 1950s, pacemakers began to be used in children recovering from heart surgery. They plugged into a wall socket, so when the power went out, so did the pacemaker. In 1958, the first fully implantable pacemaker was placed. The first one worked for 3 hours, the second for 2 days.

Electrical brain stimulation was first used during the first half of the 19th century by pioneering researchers such as Luigi Galvani (1173-1831) and Pierre Flourens (1794-1867) to localize function in the brain, following the discovery by Luigi Rolando (1737-1798) that nerves and muscles were electrically excitable. In 1967, eight patients with intense chronic cutaneous pain, sensory nerves or roots were stimulated, and four of them, who had peripheral nerve disease, experienced temporary pain relief.

  • Dr. Krames said. "The same year, a spinal cord stimulator to the dorsal column was used for the first time, by my team. I knew from the outset that I was getting involved in a field that someday would become the future of medicine. As Walt Whitman said in the 1880s, 'I sing the body electric.'"

Deep brain stimulation (DBS) was first employed for the treatment of Parkinson's disease by Alim Louis Benabid and colleagues, who stimulated the subthalamic nucleus in 2009. DBS is used in cases of depression, obsessive-compulsive disorder, and essential tremor.

  • Depression: DBS targets the ventral capsule/ventral striatum, nucleus accumbens, subgenual cingulate cortex area 25, inferior thalamic peduncle, rostral cingulate cortex area 24, and lateral habenula.
  • Obsessive-compulsive disorder: DBS targets the anterior limb of the internal capsule, ventral striatum/ventral capsule, nucleus accumbens, nucleus subthalamicus, and inferior thalamic peduncle.
  • Essential tremor: DBS targets the ventral intermediate nucleus of thalamus and posterior subthalamic area.

Future Directions

Theorists of bioelectric medicine posit that all body functions are electrochemical, and therefore carry an electric footprint. They propose electric treatment of disease, called electroceuticals, which deliver electrical impulses targeted the neural circuits that regulate organs and functions. The electroceutical homes in on discrete components of the nervous system, such as individual neurons, in a specific circuit, modulating the action potentials that flow through these neurons.

Electrical stimulation may come to play a role in:

  • Glucose control and diabetes, via stimulation of calcitonin gene-related peptide (CGRP) release from transient receptor potential cation channel subfamily V member I (TRPVI, also known as the capsaicin receptor) neuron and the vanilloid receptor protein-1. TRPVI releases CGRP, which, in turn, raises glucose release.
  • Cytokine-mediated inflammatory diseases such as arthritis, psoriasis, and colitis. The cytokine theory of disease posits that balanced cytokine production is balanced in a state of health (homeostasis). Overproduction of some cytokine comparisons causes diseases ranging from mild to lethal. Arthritis is an example of a disease in which the cytokine tumor necrosis factor, interleukin 1, and high-mobility group protein B1 (HMGB1) are overproduced. In septic shock, lethal hemorrhagic tissue injury is mediated by overproduction of tumor necrosis factor. Vagus nerve stimulation provokes cholinergic signaling, which inhibits the release of tumor necrosis factor, interleukin 1, HMGB1, and other cytokines. The inhibition of cytokine release is termed the inflammatory reflex. Vagal nerve stimulation has been shown to ameliorate inflammation in patients with rheumatoid arthritis.

Brain interface system is composed of:

  • Neural prosthetic/implant, penetrating or surface electrodes
  • Electronics such as amplifiers and a power source
  • Decoding/encoding algorithms for interpreting brain activity or generating stimulation patterns

In paralysis, the first in-human demonstration of cursor control was in 2005; of wheelchair control in 2006.

  • Brain-Computer-Body (BCB) interfacing could one day allow complete bridging of damaged neural pathways in spine cord injury, stroke, traumatic brain injury, and other conditions.


Optogenetics is the combination of optical and molecular strategies to monitor and control designated molecular and cellular activities in tissues and cells using genetically encoded photosensitive proteins. The goal is to regain previous loss of function within living cells. Targeted excitation or inhibition confers cellular specificity and even projection specificity not feasible with electrodes, while maintaining high-precision action potentials.

A cannula is implanted into the head of the animal to guide an optical fiber to the targeted brain region. The optical fiber is coupled to a strong light source, such as a 488 nm laser diode, to bring blue or yellow light into the brain. Genetic targeting of channelrhodopsin or halorhodopsin into disease-model-relevant neurons may allow cell-specific neuromodulation and avoid inadvertent stimulation of disease-model-irrelevant neurons, as occurs with electrical stimulation. The first paper (2005) that reported on optogenetics in cultured mammalian hippocampal neurons, demonstrated expression and functionality of channelrhodopsin in neurons. The current produced by channelrhodopsin activation was sufficient to produce action potentials. Channelrhodopsin was inactivated at a low rate and recovered quickly. Results were repeated by several other labs following publication of the first paper. Optogenetics holds potential in movement disorders, Parkinson's disease, neurogenerative diseases, cancer, epilepsy, memory, inborn genetic errors, neuropathic pain syndromes, spasticity, psychiatric diseases, control of T-cell release of tumor necrosis factor, and inflammation.


Considering the potential that biolectric medicine, BCB interfacing, and optogenetics holds in conditions ranging from diabetes to paralysis, neuromodulatory medicine can be expected to exert an incalculable impact on medicine in the 21st century. As Yogi Berra said, "The future ain't what it used to be."

"My successor at the helm of Neuromodulation, Robert Levy, has done a marvelous job of growing the journal, and with it, interest in the technique," said Dr. Krames. "We in the field of neuromodulation sit on the cusp of something big. We will be medicine's future!"

Updated on: 01/02/20
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