Deep Brain Stimulation is a Screw, Not a Nail

Professor – Abraham Maslow said “When all you have is a hammer, the whole world looks like a nail”

Student – What if the world is a screw?

Deep Brain Stimulation (DBS) is arguably the most effective treatment for many neurological and psychiatric disorders. In disorders in which DBS has been applied, DBS is better than pharmaceutical or biologic treatments as DBS succeeds where the others fail. So why is DBS only offered to a small percentage of those patients who need DBS? Perhaps, it is because DBS is seen as a nail (conceptually equivalent to pharmacological or a biologic therapy) when in reality, DBS is a screw (different and more relevant than pharmaceuticals or biologics).

Perhaps we are in the midst of a Kuhnian paradigm shift, but not realizing it because of Kuhn’s observation of incommensurability (Thomas Kuhn The Structure of Scientific Revolutions, University of Chicago Press, 1962). Kuhn reasonably argued that thinkers in one paradigm cannot appreciate the concepts of the alternative paradigm. It is not an exaggeration to say that pharmacological approaches have dominated non-surgical medical disciplines, especially neurology. Non-surgical physicians have little qualms about prescribing medications, including those that are potentially highly toxic, but it seems altogether different and foreign to prescribe electricity, as in the case of DBS.

Even when physicians prescribe electricity, it is done as though electricity was the same as a pharmaceutical. When DBS is not sufficient, physicians prescribe more electricity, and when there are side effects less electricity is prescribed. The notion of levodopa equivalents in pharmacological therapies for Parkinson’s disease that subsume all the various dopamine replacement based therapies under a single concept, DBS has the erroneous notion of Total Electrical Energy Delivered (TEED). It is as though all the variations of DBS stimulation parameters can be considered from a single mechanistic perspective. DBS is far more complicated and dynamic. DBS is altogether different.

As Albus Dumbledore said “Oh, by the way. When in doubt, I find retracing my steps to be a wise place to begin. Good luck.” (The movie “Harry Potter and the Prisoner of Azkaban”, 2004). Perhaps the first real insight into the mechanisms by which the nervous system produced behavior was the notion of “animal electricity” based on the observations of Luigi Galvani (1737 – 1798, C.E.) who applied electricity to nerves and muscles. Until that time, Galen’s notion of the four humors dominated without experimental evidence but by reasoning from Aristotle’s four elements. It may have Galvani’s nephew who applied electricity to the exposed nerves of decapitated humans and causing them to move; thus inspiring Mary Shelly to write “Frankenstein”.

Even with the development of the Neuron Doctrine in the mid to late 1800’s and the identification of the neuron as the fundamental unit of neuroanatomy and (mistakenly) the fundamental unit of function, the widespread but not universally accepted notion was that neurons communicated electrically. It was not until the 1940’s that chemical neurotransmission became ascendant. Even though electric or gap junction, purely electrical transmission, was demonstrated in invertebrates in the late 1950s and in vertebrates, including human, much later; chemical neurotransmission, perhaps fortified by the remarkable abilities of neuropharmacology, still dominates thinking. The adverse effects of this mode of thinking are addressed later.

The first major implication of the dominance of chemical neurotransmission is that neurophysiology is thought synonymous with neurochemistry. In 1921, Otto Loewi (1873 – 1961, C.E.) published his work demonstrating that the application of an extract (chemical) from the heart of one frog would slow the heart rate when applied to the heart of another frog. Later, the chemical acetylcholine was found to be the active ingredient in the frog heart extract. The extract slowed the heart just as did electrical stimulation of the vagus nerve. The implication was that the effects of the electrical stimulation of the vagus nerve were mediated by, or due to, release of acetylcholine. This inference was based on the syllogistic deductive argument that (major premise) slowing the heart is accomplished by applying acetylcholine; (minor premise) electrical activity in the vagus nerve slows the heart; thus, (conclusion) electrical activity in the vagus nerve is applying acetylcholine.

The classic example of a syllogistic deduction is: (major premise) All men are mortal; (minor premise) Socrates is a man; thus (conclusion) Socrates is a mortal. Mortal (major term) and Socrates (minor term) are linking the bridging term “men/man”. Thus, these three terms link in two premises to produce the conclusion. But what if Socrates was a very special man unlike all other men? The syllogistic deduction would not hold. If “man” in the case of Socrates, in the second premise, is different than “men”, in the first premise, there is no single bridging term. The result is the Fallacy of Four Terms.

The syllogistic deduction above relating electrical activity in the vagus nerve to the application of acetylcholine would fail, which is a consequence of the Fallacy of Four Terms, if the slowing of the heart with the application of acetylcholine was different than slowing the heart with electrical stimulation of the vagus nerve. The difference can be seen in the time course of the effects. The application of pharmacological amounts of acetylcholine slows the heart over a long period of time, requiring for its termination the degradation of acetylcholine by the enzyme acetylcholinesterase. Slowing the heart and restoring the heart rate occurs over a matter of seconds with electrical stimulation of the vagus nerve. What is different is the time scales over which the effects occurs, in other words, the dynamics of the effects.

To be sure, neuropharmacologists might argue that the pharmacological administration of acetylcholine is not the manner by which acetylcholine normally slows the heart rate. Rather, they might argue that acetylcholine is released in very small doses over very short time scales. But that proves the point, because what is it that controls the timing and amount of acetylcholine? There is nothing in the molecule of acetylcholine that would necessarily lead to its being released in small doses over very short time periods. It is the precise control of the electrical activity of the vagus nerve that controls the effects of acetylcholine. The conflation of acetylcholine with the physiology of the vagus nerve would be like saying that electrons are the fundamental unit of function of the computer. While it is true most computers could not function without electrons, merely dumping electrons into a computer will not produce a working computer.

DBS in Parkinson’s disease is effective even when flooding the brain with industrial quantities of dopamine (either by the pro-drug levodopa or effectively by dopamine agonists). Even localized application of dopamine by fetal dopamine implants fail to normalize function, most likely because the fetal dopamine derived neurons are disconnected from the normal electronics of the brain. Thus, it is at least a logical error to equate the actions of DBS with those of dopamine agents. Then why do physicians use DBS like dopamine agents? Why do physicians view the dynamics of DBS like they do the dynamics of dopamine replacement, that is too little or too much. DBS is far more complicated. While the complexity of DBS is a challenge, it also is an opportunity, unless physicians “dumb down” DBS as though it was a drug.

An alternative paradigm or theory we at Greenville Neuromodulation Center (GNC) are working on, space permitting only a brief description, is that behavior depends on an orchestration of motor unit recruitment and de-recruitment over multiple time scales simultaneously. The basal ganglia-thalamic-cortical system drives this orchestration because the system is organized as a large network of loosely coupled reentrant nonlinear discrete oscillators over a large bandwidth of frequencies. The nonlinearities afford the network the properties of a chaotic system, while the integration of a very large number of neurons confers properties of Complex Systems. The dynamics include stochastic resonance and stochastic coherence, among others. Further, noncommensurate frequencies within the basal ganglia-thalamic-cortical oscillators allows multiple channels of information operating at different time scales allows encoding of different channels of information simultaneously. DBS is a noisy oscillator that interacts with the oscillators within the basal ganglia-thalamic-cortical system. Much work on this theory remains to be done.