A RESEARCHER'S PERSPECTIVE: We Are Witnessing a Revolution in Brain Stimulation

A RESEARCHER'S PERSPECTIVE - from Brain & Behavior Magazine, December 2022 issue



By Mark S. George, M.D.

Distinguished Professor of Psychiatry, Radiology and Neuroscience

Founding Director, Center for Advanced Imaging Research

Director, Brain Stimulation Laboratory, Psychiatry

Medical University of South Carolina Member,

BBRF Scientific Council

2008 BBRF Falcone Prize for Outstanding Achievement in Affective Disorders Research

1998 BBRF Independent Investigator grant

1996 BBRF Young Investigator grant

The field of brain stimulation is a fascinating one. It involves psychiatry and neurology, neuroscience, in some cases neurosurgery, as well as cognitive neuroscience and a whole world of bioengineering. My journey began with a BBRF grant which was given to me 26 years ago.

It has been wonderful to be able to see a revolution occur in this field. In this article, I want to try to give you a sense of this. I’ll focus on TMS—transcranial magnetic stimulation— which is the technology that I’ve used for most of my career.

If you take electricity and run it through a coil, the electricity creates a magnetic field. The skull and skin stop electricity from passing through to the brain, but magnetic fields pass unimpeded. When these fields encounter a nerve cell, they will cause it to depolarize—its electrical charge changes, which is part of the process that causes a neuron to “fire.” So we’re electrically stimulating the brain, but using a magnet to be able to do so. It’s really a wonderful technology.

I first stumbled onto this early in my career, when I was in London. I later moved to the National Institutes of Health and my boss there, Dr. Robert Post, who is now one of my colleagues on BBRF’s Scientific Council, gave me license to do a clinical trial. I was able to do the first 2-week double-blind, randomized trial of the method we now call TMS.

Later, I moved to Charleston, South Carolina, to take a position on the faculty of the Medical University of South Carolina. My lab was supported in part by BBRF, so from the very beginning, BBRF was important in the research that led to our first clinical trial of TMS and then other interventions.

I’ll never forget when I “unblinded” the first double-blind study—the moment we could really interpret the results— and saw a TMS antidepressant effect. I was excited but also scared. My worry was that I would make wrong decisions or something would happen that would stop this technology from becoming a widespread treatment.

This is where BBRF was important. They gave money when no one else would. There was no “brain stimulation industry” at that time. I did not pursue getting a patent and thus there was not a patent that industry could organize around to then do the initial clinical trials. The NIH was not keen on the idea in those early days and was even actively against funding TMS, or even talking about it. There were no FDA-approved indications for TMS. But we’ve come a long way since then. It is fair to say we have really changed the face of neuropsychiatry now with the success of TMS.

I’ll devote most of this piece to TMS. But before I do, it’s important to mention that in addition to TMS, there are a variety of brain stimulation techniques in use today. You may have heard of electroconvulsive therapy, or ECT, which is the grandmother of the whole field. In ECT, a mild electric current is used to cause a brief seizure in the brain. This seizure often has therapeutic effects, perhaps most notably in severely depressed “refractory” patients who have not been helped by other forms of therapy. The patient is placed under anesthesia during the treatment. ECT is most often used in depression, but also in catatonia, schizophrenia and bipolar disorder.

Another form of brain stimulation you may have heard of is called deep brain stimulation (DBS), where we surgically implant a wire in the brain to deliver stimulation. This has proven to be really important for the treatment of Parkinson’s disease, dystonia (involuntary muscle contractions), and essential tremor. It has also been used experimentally to treat severe, refractory depression, an application pioneered by Dr. Helen Mayberg, another of my colleagues on BBRF’s Scientific Council.

tDCS—transcranial direct-current stimulation—is another stimulation technology in which you pass electrical current through the brain, but unlike DBS, it is delivered non-invasively Then, too, there has been an explosion of activity in investigating different ways to stimulate the vagus nerve, which is the body’s most important nerve pathway connecting the brain with the heart, lungs, and digestive tract. There are FDAapproved indications for VNS—vagus nerve stimulation—for epilepsy, depression, and obesity. This can work either invasively with a wire implanted in the neck or noninvasively with a device that you hold up to the neck or connect through the ear.

A new technology called pulsed ultrasound is also being used experimentally to stimulate the brain. I’ll discuss it in more detail later in the article.

All these technologies will be improved in the future. And it will not be a matter simply of deciding to treat patients either with talk therapy or medications or brain stimulation. Rather, combinations seem likely. The key appears to be our ability to have a beneficial impact on synaptic plasticity—the ability of neurons to change the strength of their connections.

TMS AS ‘EXERCISE’ FOR THE BRAIN

What do we know about how TMS works? What does it do to the brain? We’ve put people in the [MRI] scanner. We’ve learned that when we’re stimulating a part of the brain with TMS, we’re actually just exercising it, like going to the gym. And that may be why results are not immediate— they’re dose-dependent. Like going to the gym, you don’t really get results after the first session, but over time. If it’s true that we’re making the brain do what it does naturally in an organized way, like exercise, you can see why TMS would have the excellent safety profile that it does. It’s remarkably safe.

In the classic protocol we devised years ago that led in 2009 to FDA approval for TMS in depression, the treatment is given daily, five times a week for 4 to 6 weeks. Each stimulation session lasts about 40 minutes and the patient, who receives the treatment while reclining in a chair, can return to normal activities after the session ends. The treatment for depression now commonly used involves delivering repetitive magnetic pulses, and for this reason it’s called repetitive TMS or rTMS. Variations include intermittent theta-burst stimulation (iTBS), in which pulses are delivered at a different frequency, enabling a substantial reduction in the time of each treatment session—each is just a few minutes in duration.

There have been some exciting advances with TMS and one in particular seems to supply strong evidence of the relationship between “dose” and effectiveness. My former student, now a colleague and friend, Dr. Nolan Williams, at Stanford University, has tested the idea of accelerating TMS treatments and significantly increasing the total dosage given during a course of therapy. Dr. Williams and colleagues have developed Stanford Neuromodulation Therapy, (referred to as SNT or SAINT), a protocol which instead of giving one TMS treatment per day over 4–6 weeks in sessions typically lasting about 38 minutes, delivers 10 treatments in one day—each session lasting just a few minutes—for 5 days running. The patient receives a great deal of stimulation concentrated in just those 5 days.

With SNT, Dr. Williams finds that he gets from 79% to almost 90% remission—an elimination of depression symptoms—in people who’ve tried and failed multiple other forms of antidepression therapy. And the patients are getting well very quickly—within the week that they are treated. Because of the rapid action, there is the thought that this accelerated and intensified type of TMS can be useful in inpatient psychiatric units and emergency rooms, to treat people at high risk of suicide. This is a really important advance with TMS. BBRF funded this work with two Young Investigator grants to Dr. Williams. [This technology has just been approved by the FDA]

We’ve learned that in trying to assess how well TMS is likely to work in a patient and how it might be combined with other treatments, we need to take into consideration what’s going on in the brain while we stimulate. Specifically, we find that active circuits are more easily changed and modified by TMS than those that are not. An example of why this is important is the use of TMS in obsessive compulsive disorder (OCD). The FDA has approved TMS for OCD. But we find that TMS alone often doesn’t work. For it to work, you have to deliver the stimulation while someone is actively obsessing or wanting to do their compulsion. Last year, we received FDA approval for smoking cessation. Again, we find that you have to have people craving a cigarette while you stimulate in order for TMS to work.

I think any brain disorder where we understand the circuitry involved in its causation and we can reach that circuitry with TMS is a candidate for eventually being treated by TMS. Ten years from now, how many TMS indications will we have? It could be as many as 10 or 15. Right now TMS is approved for depression, anxious depression, OCD, and smoking cessation. Future indications include suicidal behavior as well as alcohol withdrawal and abstinence, pain relief, and stroke recovery. It may also find application in reducing positive symptoms like hallucinations as well as negative symptoms like cognitive dysfunction in schizophrenia. The list will, I think, keep growing and growing year by year.

I mentioned the possibility of intervening with TMS in circuits causally linked with psychiatric and other illnesses. Some really interesting research by BBRF-funded researcher Dr. Shan Siddiqi and Dr. Michael Fox at Harvard sheds light on such circuits. They have figured out that under the big umbrella of “depression,” there are two different types of patients—those who are “dysphoric” and those who are “anhedonic.” Dysphoria refers to a feeling of unease, discomfort, anxiety. These patients often have physical symptoms. Anhedonia involves loss of interest in pleasurable activities—patients sleep a lot, lack energy. If you look at what parts of the brain are dysfunctional in these different kinds of patients, you find different circuits that are causally associated with dysfunction. This data can inform the targeting of TMS treatments—different targets for different individuals based on their type of depression. This idea is now being tested. It’s a psychiatrist’s dream—knowing exactly where you’d want to place the magnetic coil to have the greatest likelihood of reducing a patient’s symptoms.

Another innovation in brain stimulation therapy came to fruition in the last year, when the FDA approved a cervical vagus nerve stimulation (VNS) device for use in stroke patients. Say you can’t move your right arm because of a stroke. Well, you go to your physical therapist and you have this VNS device implanted in your neck. The therapist, while you’re trying to move your hand, will stimulate your vagus nerve. And so you’re being stimulated while moving. This pairing of VNS with the behavior you’re trying to address seems to work. People with the device are able to recover from the stroke much better than those without it. We are also testing VNS delivered noninvasively, with a device that can be placed against the neck or over the ear.

This brings together brain stimulation with Eastern medicine, specifically acupuncture. Years ago we learned that there are acupuncture areas that have effects similar to vagus nerve stimulation. We can now target those areas electrically to stimulate the vagus nerve. As I just mentioned it is now FDA-approved for stroke rehab in adults. Could this work as well in newborns? This is the pioneering work of Dr. Dorothea Jenkins. Many babies are born with brain damage. The first thing a newborn needs to learn is to how to suck, swallow and breathe— the complicated skill of feeding. Those infants that cannot learn how to feed have to be given a feeding tube in the stomach before they can go home from the hospital.

Dr. Jenkins has delivered stimulation to the vagus nerve while the baby is learning to feed. This has enabled Dr. Jenkins to take half of the kids who are supposed to have a feeding tube and with this approach actually teach them how to feed so that it is unnecessary. We’re now trying to apply this technology to children with cerebral palsy while they’re trying to learn to move, as well as in children with autism spectrum disorder. Both involve stimulating the brain via the vagus nerve to promote learningrelated brain plasticity.

THE FUTURE OF STIMULATION

Is there a holy grail? What is the best possible brain stimulation tool?

I prefer noninvasive stimulation. It means we don’t have to do surgery. The ideal tool will enable us to stimulate deep in the brain or superficially—both. I want it to be inexpensive. I’d love for it to be portable. And I want it to just modulate the brain and not destroy brain tissue.

I’m working right now with a new stimulation delivery method called pulsed ultrasound. It uses the same technology as ultrasound that enables us to “see” a baby in the womb, but instead of continuously generating the sound waves, we pulse them. For reasons we still don’t understand, when you pulse ultrasound at a human neuron, it causes it to depolarize. In other words, the sound waves stimulate the neuron by changing its electrical activity.

You can use ultrasound to ablate the brain—destroy cells as a means of treating, for example, essential tremor (also FDA-approved). However, in our experiments, we use a much milder form of ultrasound that doesn’t destroy tissue. We’re just modulating the activity of neurons and circuits. Initially, being scientifically skeptical of any new way of stimulating the brain, I suggested that we should first use ultrasound to target the thalamus, which is deep in the brain. The aim was to see if we could reduce sensations of pain, which are modulated by the thalamus. I reasoned that if pulsed ultrasound can noninvasively modulate the thalamus and cause changes in pain perception, then it might have many other uses.

We designed a study where we stimulated the thalamus of healthy adults while they were inside the MRI scanner. And what we found in our first study was that we were able to modulate pain by stimulating the thalamus with ultrasound. We still need to do a lot more work in terms of targeting and optimal dosing, as well as looking at what happens over time and to see how long beneficial effects last. But at least in my mind, it does seem that ultrasound can go deep into the brain, non-invasively. We’re a little further along now with ultrasound than where I was back in 1996 when we were developing TMS, so we’ve made a start and are doing small clinical trials right now. There’s still a lot of work needed before this could become a therapy.

In reviewing the explosion of new ways to stimulate the brain. I’ve talked about electrical stimulation, magnetic stimulation, and stimulating with sound. I haven’t talked about light. There’s really interesting research being done in “focal pharmacology,” guided by brain stimulation, in which a medication is delivered inside a carrier molecule, and then is guided to its target by brain stimulation technology. You release the medicine just in that part of the brain where you want it to go. This way, there are no “off-target” effects.

So we have so many new ways to stimulate the brain. However, the rate-limiting step in developing new treatments involving brain stimulation is not ideas or technology. It’s actually people—people who know how to do clinical trials, who know patients, and who can do the initial small studies testing whether these technologies can be used as therapies. And that’s where BBRF and other grant-giving agencies are so very, very important. Given sufficient research funding, I feel that for brain stimulation, the sky is the limit. But we need to grow and invest in the young researchers of the future.

Written By Peter Tarr, Ph.D.

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