tDCS Peripheral Nerve Stimulation: A Neglected Mode of Action?

In the November 13, 2020 episode of Shark Tank (Season 12, Episode 5), two earnest entrepreneurs, Ken and Allyson, try to persuade five investors, the “sharks,” to buy into their company. The entrepreneurs sell LIFTiD, a device that applies a small steady current to the forehead. Ken said it’s supposed to improve “productivity, focus, and performance.” Allyson claimed it’s a “smarter way to get a… boost of energy.”

The device is based on transcranial direct current stimulation (tDCS). In 2009 I published an editorial in the journal Clinical Neurophysiology to accompany a paper appearing in the same issue by Pedro Miranda and his colleagues (Clin. Neurophysiol., Volume 120, Pages 1183–1187, 2009), in which they calculated the electric field in the brain caused by a 1 mA current applied to the scalp. I wrote

Although Miranda et al.’s paper is useful and enlightening, one crucial issue is not addressed: the mechanism of tDCS. In other words, how does the electric field interact with the neurons to modulate their excitability? Miranda et al. calculate a current density in the brain on the order of 0.01 mA/cm², which corresponds to an electric field of about 0.3 V/m (a magnitude that is consistent with other studies (Wagner et al., 2007)). Such a small electric field should polarize a neuron only slightly. Hause’s model of a single neuron predicts that a 10 V/m electric field would induce a transmembrane potential of 6–8 mV (Hause, 1975), implying that the 0.3 V/m electric field during tDCS should produce a transmembrane potential of less than 1 mV. Can such a small polarization significantly influence neuron excitability? If so, how? These questions perplex me, yet answers are essential for understanding tDCS. Detailed models of the cortical geometry and brain heterogeneities may be necessary to address this issue (Silva et al., 2008), but ultimately the response of the neuron (or network of neurons) to the electric field must be included in the model in order to unravel the mechanism. Moreover, because the effect of tDCS can last for up to an hour after the current turns off (Nitsche et al., 2008), the mechanism is likely to be more complicated than just neural polarization.

van Boekholdt et al. (2021)

My participation in the field of transcranial direct current stimulation started and ended with writing this editorial. However, I still follow the literature, and was was fascinated by a recent article by Luuk van Boekholdt and his coworkers in Molecular Psychiatry (Volume 26, Pages 456–461, 2021). Their abstract says

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method widely used by neuroscientists and clinicians for research and therapeutic purposes. tDCS is currently under investigation as a treatment for a range of psychiatric disorders. Despite its popularity, a full understanding of tDCS’s underlying neurophysiological mechanisms is still lacking. tDCS creates a weak electric field in the cerebral cortex which is generally assumed to cause the observed effects. Interestingly, as tDCS is applied directly on the skin, localized peripheral nerve endings are exposed to much higher electric field strengths than the underlying cortices. Yet, the potential contribution of peripheral mechanisms in causing tDCS’s effects has never been systemically investigated. We hypothesize that tDCS induces arousal and vigilance through peripheral mechanisms. We suggest that this may involve peripherally-evoked activation of the ascending reticular activating system, in which norepinephrine is distributed throughout the brain by the locus coeruleus. Finally, we provide suggestions to improve tDCS experimental design beyond the standard sham control, such as topical anesthetics to block peripheral nerves and active controls to stimulate non-target areas. Broad adoption of these measures in all tDCS experiments could help disambiguate peripheral from true transcranial tDCS mechanisms.

When the sharks tried the LIFTiD device, they each could feel a tingling shock on their scalp. If van Boekholdt et al.’s suggestion is correct, the titillation and annoyance caused by that shock might be responsible for the effects associated with tDCS. In that case, the method would work even if you could somehow make the skull a perfect insulator, so no current whatsoever could enter the brain. I like how van Boekholdt suggests specific, simple experiments that could test their hypothesis.

If you’re trying to buy a device to improve brain performance, you might not care if it works by directly stimulating the brain or just by exciting peripheral nerves. In fact, you might be able to save money by hiring someone to poke you in the back every few seconds. Do whatever it takes to focus your attention.

None of the sharks invested in LIFTiD. My favorite shark, Mark Cuban, claimed the entrepreneurs “tried to sell science without using science.” I couldn’t have said it better myself. 

LIFTiD Neurostimulation Personal Brain Stimulator; https://www.youtube.com/watch?v=hFzihXprRUM

Currents of Fear: In Which Power Lines Are Suspected of Causing Cancer

Voodoo Science,
by Robert Park

These days—when so many people believe crazy conspiracy theories, refuse life-saving vaccines, promote alternative medicine, fret about perceived 5G cell phone hazards, and postulate implausible microwave weapons to explain the Havana Syndrome—we need to understand better how science interacts with society. In particular, we should examine past controversies to see what we can learn. In this post, I review the power line/cancer debate of the 1980s and 90s. I remember it well, because it raged during my graduate school days. The dispute centered on the physics Russ Hobbie and I describe in Chapter 9 of Intermediate Physics for Medicine and Biology. 

To tell this tale, I’ve selected excerpts from Robert Park’s book Voodoo Science: The Road from Foolishness to Fraud. The story has important lessons for today. Enjoy!

Currents of Fear: In Which Power Lines Are Suspected of Causing Cancer

In 1979, an unemployed epidemiologist named Nancy Wertheimer obtained the addresses of childhood leukemia patients in Denver and drove about the city looking for some common environmental factor that might be responsible. What she noticed was that many of the homes of victims seemed to be near power transformers. Could it be that fields from the electric power distribution system were linked to leukemia? She teamed up with a physicist named Ed Leeper, who devised a “wiring code” based on the size and proximity of power lines to estimate the strength of the magnetic fields. Together they eventually produced a paper relating childhood leukemia to the fields from power lines…

In June of 1989, The New Yorker carried a new three-part series of highly sensational articles by Paul Brodeur… on the hazards of power-line fields…. The series reached an affluent, educated, environmentally concerned audience. Suddenly, Brodeur was everywhere: the Today show on NBC, Nightline on ABC, This Morning on CBS, and, of course, Larry King Live on CNN. In the fall, Brodeur published the New Yorker series as a book with the lurid title Currents of Death. A new generation of environmental activists, led by mothers who feared for their children’s lives, demanded government action…

By [1995], sixteen years had passed since Nancy Wertheimer took her historic drive around Denver. An entire industry had grown up around the power-line controversy. Armies of epidemiologists conducted ever larger studies; activists organized campaigns to relocate power lines away from schools; the courts were clogged with damage suits; a half dozen newsletters were devoted to reporting on EMF [electromagnetic fields]; a brisk business had developed in measuring 60 Hz magnetic fields in homes and workplaces; fraudulent devices of every sort were being marketed to protect against EMF; and, of course, Paul Brodeur’s books were selling well…

It was into this climate that the Stevens Report was released by the National Academy of Sciences in 1996 with it unanimous conclusion that “the current body of evidence does not show that exposure to these fields presents a human health hazard.”… The chair of the review panel, Charles Stevens, a distinguished neurobiologist with the Salk Institute, [explained] the difficulty of trying to identify weak environmental hazards. Scientists had labored for seventeen years to evaluate the hazards of power-line fields; they had conducted epidemiological studies, laboratory research, and computational analysis. “Our committee evaluated over five hundred studies,” Stevens said, “and in the end all we can say is that the evidence doesn’t point to these fields as being a health risk…”

On July 2, 1997, the National Cancer Institute (NCI) finally announced the results of its exhaustive epidemiological study, “Residential Exposure to Magnetic Fields and Acute Lymphoblastic Leukemia in Children”… It was the most unimpeachable epidemiological study of the connection between power lines and cancer yet undertaken. Every conceivable source of investigator bias was eliminated. There were 638 children under age fifteen with acute lymphoblastic leukemia enrolled in the study along with 620 carefully matched controls, ensuring reliable statistics. All measurements were double blind… [The study] concluded that any link between acute lymphoblastic leukemia in children and magnetic fields is too weak to detect or to be concerned about. But the most surprising result had to do with the proximity of power lines to the homes of leukemia victims: the study found no association at all. The supposed association between proximity to power lines and childhood leukemia, which had kept the controversy alive all these years, was spurious—just an artifact of the statistical analysis. As is so often the case with voodoo science, with every improved study the effect had gotten smaller. Now, after eighteen years, it was gone completely.

 

Power Line Fears, https://www.retroreport.org/video/power-line-fears

 

The Bragg Peak (Continued)

In last week’s post, I discussed the Bragg peak: protons passing through tissue lose most of their energy near the end of their path. In Chapter 16 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I present a homework problem in which the student calculates the stopping power (energy lost per distance traveled), S, as a function of depth, x, given a relationship between stopping power and energy, T. This problem is a toy model illustrating the physical origin of the Bragg peak. Often it’s helpful to have two such exercises; one to assign as homework and one to work in class (or put on an exam). Here’s a new homework problem similar to the one in IPMB, but with a different assumption about how stopping power depends on energy.

Section 16.10

Problem 31 ½. Assume the stopping power of a particle, S = −dT/dx, as a function of kinetic energy, T, is S = S_o e^−T/T_o. 

(a) What are the units of S_o and T_o? 

(b) If the initial kinetic energy at x = 0 is T_i, calculate T(x). 

(c) Determine the range R of the particle as a function of T_o, S_o, and T_i. 

(d) Plot S(x) vs. x. Does this plot contain a Bragg peak? 

(e) Discuss the implications of the shape of S(x) for radiation treatment using this particle.

The answer to part (d) is difficult, because your conclusion is different depending on the relative magnitude of T_i and T_o. You might consider adding a part (f)

(f) Plot T(x), S(x), and R(T_i) for T_i >> T_o and for T_i << T_o.

The case T_i >> T_o has a conspicuous Bragg peak; the case T_i << T_o doesn’t. 

The homework problem in IPMB is more realistic than this new one, because Fig. 15.17 indicates that the stopping power decreases as 1/T (assumed in the original problem) rather than exponentially (assumed in the new problem). This changes the particle’s behavior, particularly at low energies (near the end of its range, in the Bragg peak). Nevertheless, having multiple versions of the problem is useful. 

The answer to part (e) is given in IPMB.

Protons are also used to treat tumors... Their advantage is the increase of stopping power at low energies. It is possible to make them come to rest in the tissue to be destroyed, with an enhanced dose relative to intervening tissue and almost no dose distally.

 Enjoy!

The Bragg Peak

In Chapter 16 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I discuss the Bragg peak.

Protons are also used to treat tumors (Khan 2010, Ch. 26; Goitein 2008). Their advantage is the increase of stopping power at low energies. It is possible to make them come to rest in the tissue to be destroyed, with an enhanced dose relative to intervening tissue and almost no dose distally (“downstream”) as shown by the Bragg peak in Fig.16.47.

Energy loss versus depth for a 150 MeV proton beam in water, with and without straggling (fluctuations in the range). The Bragg peak enhances the energy deposition at the end of the proton range. Adapted from Fig. 16.47 in Intermediate Physics for Medicine and Biology.

William Henry Bragg

Sir William Henry Bragg (1862 – 1942) was an English scientist who shared the 1915 Nobel Prize in Physics with his son Lawrence Bragg for their analysis of crystal structure using X-rays. In 2004, Andrew Brown and Herman Suit published an article commemorating “The Centenary of the Discovery of the Bragg Peak” (Radiotherapy and Oncology, Volume 73, Pages 265-268).

In December 1904, William Henry Bragg, Professor of Mathematics and Physics at the University of Adelaide and his assistant Richard Kleeman published in the Philosophical Magazine (London) novel observations on radioactivity. Their paper “On the ionization of curves of radium,” gave measurements of the ionization produced in air by alpha particles, at varying distances from a very thin source of radium salt. The recorded ionization curves “brought to light a fact, which we believe to have been hitherto unobserved. It is, that the alpha particle is a more efficient ionizer towards the extreme end of its course.” This was promptly followed by further results in the Philosophical Magazine in 1905. Their finding was contrary to the accepted wisdom of the day, viz. that the ionizations produced by alpha particles decrease exponentially with range. From theoretical considerations, they concluded that an alpha particle possesses a definite range in air, determined by its initial energy and produces increasing ionization density near the end of its range due to its diminishing speed.

Although Bragg discovered the Bragg peak for alpha particles, the same behavior is found for other heavy charged particles such as protons. It is the key concept underlying the development of proton therapy. Brown and Suit conclude

The first patient treatment by charged particle therapy occurred within a decade of Wilson’s paper [the first use of protons in therapy, published in 1946]. Since then, the radiation oncology community has been evaluating various particle beams for clinical use. By December 2004, a century after Bragg’s original publication, the approximate number of patients treated by proton–neon beams is 47,000 (Personal communication, Janet Sisterson, Editor, Particles) [over 170,000 today]. There have been several clear clinical gains. None of these would have been possible, were it not for the demonstration that radically different depth dose curves were feasible.

Alan Magee and the St. Nazaire Railroad Station

Alan Magee. Reproduced from the
website www.americanairmuseum.com.

On January 3, 1943, airman Alan Magee fell 22,000 feet (6700 meters, or about 4 miles) without a parachute from a damaged B-17 Flying Fortress and survived. How’d he do it?

Let’s examine Magee’s fall using elementary physics. Homework Problem 29 in Chapter 2 of Intermediate Physics for Medicine and Biology explains how someone falling through the air reaches a steady-state, or terminal, speed. A typical terminal speed, v, when skydiving is about 50 m/s. This may be a little slower than average, but v decreases with mass and ball turret gunners like Magee were usually small. Skydivers will reach their terminal speed after about 20 seconds. Magee fell for much longer than that, so starting four miles up didn’t matter. He could have begun forty miles up and his terminal speed would have been the same (presumably he would have suffocated, but that’s another story).

When falling, what kills you is the sudden deceleration when you hit the ground. Suppose you’re traveling at v = 50 m/s and you hit a hard surface like cement. You come to a stop over a distance, h, of a few centimeters (a person isn’t rigid, so there would be some distance that corresponds to the body splatting). Let’s estimate 10 cm, or h = 0.1 m. If the acceleration, a, is uniform, we can use an equation from kinematics to calculate a from v and h: a = v²/(2h) = 50²/0.2 = 12,500 m/s². This is about 1250g, where g is the acceleration of gravity (approximately 10 m/s²).

How much acceleration can a person survive? It’s hard to say. Some roller coasters can accelerate at up to 3g and you feel a thrill. Astronauts in the Mercury space program experienced about 10g during reentry and they survived. Flight surgeon John Stapp withstood 46g on a rocket sled, but that is probably near the maximum. Clearly 1250g is well over the threshold of survivability. You would die.

So, how did Magee survive? He didn’t hit cement. Instead, he crashed through the glass ceiling of the St. Nazaire railroad station. Most sources I’ve read claim that shattering the glass helped break his fall. Maybe, but I have another idea. Some of the articles I’ve examined have German soldiers finding Magee alive on the station floor, but others say he was found tangled in steel girders. Below is a picture of the railroad station as it looked during World War II. 

The Railroad Station in St. Nazaire, France. Modified from a photo posted by @ron_eisele on Twitter.

 

Notice the structures below the glass ceiling. I wouldn’t call them girders or struts. To me they look like a web of steel cables or ties. My hypothesis is that this web functioned as a net. Suppose Magee landed on one of the ties and it deflected downward, perhaps dragging part of the ceiling with it, or pulling down other ties, or breaking at one end, or stretching like a bungee cord. All this pulling and breaking and stretching would reduce his deceleration. Let’s guess that he came to rest about three meters below where he first hit a tie. Now his acceleration (assuming it’s uniform) is a = 50²/6 = 417 m/s², or about 42g. That’s a big deceleration, but it may be survivable. You would expect him to be hurt, and he was; he suffered from several broken bones, damage to a lung and kidney, and a nearly severed arm.

If my hypothesis is correct, the shattering of glass had little or nothing to do with breaking Magee’s fall. I’m sure it made a loud noise, and must have given the accident a dramatic flair, but the glass ceiling may have been irrelevant to his survival.

I don’t think we can ever know for sure why Magee didn’t die, short of building a replica of the train station, dropping corpses (or, more hygienically, crash dummies) through the roof, and video recording their fall. Still, it’s fun to speculate.

After the crash, what happened to Magee? He was captured, became a prisoner of war, and was treated for his injuries. In May 1945 the war in Europe ended and he was freed. He returned to the United States and lived another 58 years. He was awarded the Air Medal and a well-earned Purple Heart. Alan Magee's survival represents a fascinating example of physics applied to medicine and biology.

Triumph of Victory. A reenactment of Alan Magee’s fall.

Don’t expect much dialogue.

https://www.youtube.com/watch?v=WEZ97XsU2wQ&t=109s