A Little History of Neuromodulation

Design by Amy Wang

Frog Legs and Frankenstein

The story I’m about to tell you starts in the late 1780s, when the 43-year-old Renaissance man Luigi Galvani, along with his wife, Lucia, serendipitously discovered that electrical stimulation of a frog’s legs caused it to kick. His discovery led to a flurry of scientific interest in what was originally called bioelectricity, and what we today call electrophysiology — the study of the electrical properties of organisms from the cell to the organ level.

While I won’t bore you with the details of their work, I will tell you that the Galvanis had made perhaps the biggest contribution to neuroscience up until that point, without even realizing it. They had discovered that there was some deep connection between electricity, this abstract phenomenon that we saw in lightning and that could be harnessed to generate power, and life. Decades of investigation would lead to the discovery that individual cells could propagate electrical signals down their length in the form of action potentials — these are the body’s neurons. The famous biophysicists Hodgkin and Huxley would go on to win the Nobel Prize for their detailed mathematical analysis and modeling of the electrical properties of neurons, the so-called Hodgkin-Huxley model.

The connection between the nervous system and electricity even made its way into popular culture when, in 1816, inspired by reports of the Galvanis’ work from 40 years prior, a young Mary Shelley imagined a story of a mad scientist using electricity to reanimate a corpse — the story eventually became a well-known tale: Frankenstein. Later this year, the 4th installment of the Matrix series will be released — a story that tells of a time when human minds will be harnessed for bioelectricity, a time when humans can be directly connected to computers and live in a virtual space.

But here, I aim not to bring you tales of sci-fi cyborgs and brainwashing computer chips — instead, I want to take us on a tour through the ways we can use electromagnetism to stimulate and heal damaged brains. We’ll look at some examples of the ways we can use technology to change the brain in ways we don’t even fully understand. I hope to impart to you, if nothing else, a deeper sense of appreciation for the technology that exists around us today, as well as the ingenuity of those physicians, scientists, and engineers, who work in these cutting-edge frontiers of medicine.

Welcome to the world of neurostimulation.

Neurological Disease

Whether or not the sentiment is justified, it is often said that what separates us from the rest of the animal kingdom is our capacity for conscious thought. If this is the case, it must be true that there is something uniquely human about our brains, some feature that makes us special. Agree or disagree, it is a fact that the human brain is one of the most complex biological machines we have encountered in the world — indeed, there is still so much we have to learn about it.

This, in my opinion, is what makes neurological disease so devastating. Patients with Alzheimer’s, Parkinson’s, Dementia — and even psychiatric disorders such as depression or anxiety — lose control and autonomy over that special aspect of our humanity. I mean not to say these conditions make someone any less human — on the contrary, they represent the human condition best by showing us how delicate the balance is between healthy and unhealthy brains.

Brain disorders can usually be traced to “faulty wiring”. While the causes are deeper, most manifest in the way of neurobiological circuitry performing differently than is expected. One classic example is epilepsy, where random electrical disturbances send patients into life-threatening seizures. To predict the onset of epileptic seizures and treat them is among the holy grails of neurology, but the brain is hard to study.

How do we look into brains, then?

Back in the old days, they’d just cut your head open. Of course, we can’t do that anymore, not that that provides the best information anyways. No, the best way to study the brain is when it’s hard at work, and numerous medical tools have been developed to study the basic physiology of the brain.

Perhaps most commonly used are MRI, CT, and PET scans. These scans are used for a variety of imaging purposes, but they’ve made their way into staple positions in the world of neuroimaging.

The technical details of each of these techniques are interesting because of the quality and quantity of information that they now afford us, but perhaps beyond the scope of my aims in this piece. What I will say is that each provides different and unique perspectives on the structure and function of the brain. Techniques like fMRI can study changes in blood flow to regions of the brain during select activities, a feature that has allowed us to image which areas of the brain are associated with different cognitive processes and difficulties. The advent of computerized reconstructive methods has allowed us to hone into brain structure with far greater detail than previously allowed, making neuroimaging an incredibly rich field.

But new technology hasn’t just given us an inside look at the brain. It’s also given us a toolbox to therapeutically target areas of the brain. These neuromodulatory tools, though new to the game relatively speaking, are pushing the ways we treat disorders in totally new ways that exploit the key connection between electromagnetism and brain physiology. While there are so many new tools out there, the two I want to discuss here are Deep Brain Stimulation (DBS) and Transcranial Magnetic Stimulation (TMS).

Deep Brain Stimulation

DBS is very commonly used to alleviate symptoms of Parkinson’s Disease in patients for whom medication is no longer sufficient. The principle is simple — carefully insert electrodes into specific areas of the brain and inject directed pulses of current. There is no consensus on how exactly this seemingly gruesome technique works, but plenty of research to suggest that it does.

DBS was “born” in the 50s when unethical studies were done on psychiatric patients to “cure them”. Tantamount to invasive electroshock therapy, these patients were often not cured, and the results were fairly inconclusive. Though we would be remiss in ignoring this early past of DBS, most scholars note that its modern instance was first developed by Alim Benabid, a French-Algerian neurosurgeon who first used DBS to alleviate Parkinsonian symptoms.

When Parkinson’s Disease Patients show signs that their current dose of medication does not seem to effectively manage their symptoms, they are often recommended for DBS surgery. Their physicians will decide upon ideal targets for DBS, generally in one of four areas of the brain (those in bold are most frequently used):

• Globus Pallidus Internus
• Subthalamic Nucleus
• Thalamus
• Pedunculopontine Nucleus

Upon inserting electrodes into some of these specific regions, small current pulses are delivered. This has the effect of somehow “resetting” the electrical activity in the region — the effects, diverse in nature, generally show relief of Parkinsonian symptoms.

DBS is now being studied as a possible intervention tool for other disorders. Most notably, some hypothesize it could be used to treat clinical depression, which could be a huge advance in our treatment of mental health disorders.

It’s important to note, of course, that DBS is an invasive neurosurgical technique. And while surgical practice has become exponentially safer over the decades, a healthy degree of caution should be employed by both physician and patient before deciding to embark on a DBS treatment plan. Ultimately, we should work to render as much benefit as possible to patients while minimizing their suffering, and sometimes nonsurgical interventions might be safer.

This brings me to the next tool in our toolkit: transcranial magnetic stimulation.

Transcranial Magnetic Stimulation

Around 10 years after the Galvanis discovered a deep connection between biology and electricity, a young Michael Faraday was born in England. He had little formal education, but taught himself the sciences and would later go on to study Chemistry under the renowned Sir Humphrey Davy, perhaps the most famous chemist of his time and the discoverer of many common metals such as sodium and potassium.

Michael Faraday conducted experiments in electrochemistry and made use of batteries extensively [incidentally, the first battery was built by Alessandro Volta, Galvani’s own student, possibly in the interest of discrediting Galvani’s work]. His research led him to the strange discovery that magnetic fields could induce electric currents and vice versa — he termed this electromagnetic induction.

Induction is now employed in almost every electronic device you can find. Most electric motors and generators operate on this basic principle: a changing magnetic field can give rise to electric currents, and changing electric currents can give rise to magnetic fields.

Of course, scientists and physicians, upon discovering the electrical nature of the brain, wanted nothing more than to apply electrical stimulation to the brains of the ill and observe the results. So was born electroshock therapy, and its more humane child transcranial electric stimulation. These therapies rely on the basic idea that applying electric voltages and electric currents across the scalp can stimulate neural activity inside the brain. Patient outcomes have been positive, but there are risks and side effects, and generally, these techniques can cause pain in the patients.

In looking for gentler treatments, Dr. Anthony Barker, a physicist and engineer by training, imagined that the principle of induction could be used to generate small currents in specific regions of the brain. This idea became what is now known as transcranial magnetic stimulation — the use of magnetic fields to induce currents in the brain.

Today, TMS has found use as an FDA-approved treatment for clinical depression. Substantial research efforts are underway to determine its utility in treating other psychiatric disorders, as well as neurodegenerative diseases. There is already some evidence that it can benefit Parkinson’s patients. In the interest of transparency, I should note that many studies performed to analyze the effectiveness of TMS do not use the most rigorous standards of blinding and placebos that might be expected of outstanding clinical research — but I think it is fair to say that TMS does show promise as an excellent therapeutic aid.

Most importantly, TMS is non-invasive. There is no head opening involved here. In other words, if we can develop TMS treatment protocols for more neurologic diseases, we can not only better patient symptoms but reduce the risk of negative surgical outcomes. I’m excited to see what the future of noninvasive neuromodulation holds because it’s clear to me we’ll be seeing some really special innovations in the coming years.

What if we could just do it ourselves?

Neuromodulatory tools are fantastic. To be able to use technology to directly manipulate specific areas of the brain such as inhibiting centers of addiction, or exciting the motor cortex, is an amazing advance in neuroscience and neurotechnology.

But some neurobiologists might tell you that you don’t have the whole story. They hope that, maybe one day, we may be able to avoid using any of these tools at all.

Our brains are known to be somewhat plastic. At early development, different regions of the brain adopt different functions, and structure and function are fluid. This is why small children, when impacted by head trauma or brain surgery, generally come out more or less fine. Some children have even had entire halves of their brains removed, and they live a generally normal life.

The child’s brain is a magnificent example of neuroplasticity — the idea that the brain can change, morph, and rewire itself to adopt as many functions as possible. Interestingly enough, as we grow older, we start to lose this ability — but it doesn’t go away completely. Some suggest that it is the brain’s neuroplasticity that allows for tools like TMS and DBS to have any utility at all. They argue that these tools directly stimulate some sort of neuroplastic rewiring to correct a faulty system.

That’s probably at least part of the story. This gives me hope that, perhaps one day, when we’ve figured out how the brain rewires itself, we can try to get it to heal itself. Psychiatrist Norman Doidge writes extensively on the topic in his aptly named book The Brain that Changes Itself and its sequel, The Brains Way of Healing. The subject matter and the extents to which Doidge takes his conclusions are generally controversial, so I will refrain from discussing them in detail — but if nothing more, they provide an excellent set of stories for all of us to get our gears turning about the wonderful capacity our brains may have to change and heal after injury.

Where to from here?

In 1798, Luigi Galvani died quietly in his home, having lost most of his money and status in the wake of a regime change in Northern Italy following the French Revolution. We stand today, over 200 years later, on the shoulders of giants who built upon his work in electrophysiology. From those early experiments on frog legs to neuromodulatory devices, our road has taken us far and I believe will take us farther.

I promised you when we began this journey that I would show you how we can change our brains. I hope I’ve convinced you of this fact. In the next few decades, I believe we’ll see the use of more neuromodulatory techniques in treating mental health. It remains to be seen whether we might see this as changing the brain, or changing the mind. I’ll let you sit with that — frankly, I struggle to answer with certainty myself.

If you take nothing else away, hold on to the appreciation you may have gained for how far we have come, and how much further we have to go, in our path to develop tools to study and heal nature’s most complex machine — the human brain.

Citations

1. Falowski, S. M., Sharan, A., Reyes, B. A., Sikkema, C., Szot, P., & Van Bockstaele, E. J. (2011). An evaluation of neuroplasticity and behavior after deep brain stimulation of the nucleus accumbens in an animal model of depression. Neurosurgery, 69(6), 1281–1290. https://doi.org/10.1227/neu.0b013e3182237346

This article was written by Sameer Rajesh, who is a senior undergraduate student at UC Berkeley studying Molecular and Cell Biology, and was edited by Oliver Krentzman and Luc LaMontagne, former Publications Leads of Neurotech@Berkeley.

This article was originally published in Neurotech@Berkeley’s Fall 2021 Edition of Mind Magazine: Change My Mind. To read more, visit neurotech.berkeley.edu/mind.html