Learning Objectives 

After reading this article, you should be able to:

1. Describe the mechanism of action of transcranial magnetic stimulation (TMS).

2. Explain the clinical considerations for determining a patient's suitability for TMS treatment. 

3. Assess the comparative advantages of TMS over other treatment modalities, such as electroconvulsive therapy (ECT) and ketamine.

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CPTR: Many of us in the psychotherapy profession have heard of transcranial magnetic stimulation (TMS), but few seem to know much about it. Can you begin by telling us what it is and how it works?

Dr. Ahmed: In the 1990s, advances in imaging technology included the development of functional MRI (fMRI). Prior to that we mainly used structural imaging, which hasn’t been particularly helpful in the field of psychiatry. This is because the brains of folks who struggle with depression and other mood disorders don’t look drastically different from those without mood disorders and, for the most part, other psychiatric disorders. But when you look at fMRI scans, they paint a different picture, allowing us to see the activity level of the various brain regions. That activity level can be increased or decreased. And in studies of folks who have major depression, those imaging scans show that there are overactive areas of the brain and underactive areas of the brain. This is where the idea of stimulating certain brain areas got started, which is where TMS comes into the picture. 

CPTR: What part of the brain seemed to be implicated in depression?

Dr. Ahmed: There is an area of the brain in the frontal lobe, called the dorsolateral prefrontal cortex, that was found to be underactive. And some researchers thought that if we could stimulate this part of the brain, increase its activity as a result, we could see what the downstream effects are on folks with depression. They also knew that they couldn’t just zap the brain with electricity like electroconvulsive therapy (ECT), which stimulates the entirety of the brain. Magnetic pulses can be used to stimulate very specific parts of the brain with pinpoint precision. A magnetic pulse can penetrate any kind of tissue and can go right through the scalp and the skull and stimulate the brain directly. 

CPTR: Can you tell us a little about the actual TMS machine?

Dr. Ahmed: Basically, the device itself is kind of like a big VCR, a box that produces a magnetic pulse that gets transmitted through—it’s like a 6-foot cord to a device that looks a bit like the head of a telephone. That device is placed on the scalp and the magnetic pulse gets shot out of the device and into the brain. 

CPTR: What do we know about what’s happening in the brain when a patient is undergoing TMS? 

Dr. Ahmed: When we stimulate the brain, we send a magnetic pulse that’s tuned to a specific frequency (ie, the rate at which we are firing the magnetic pulse). In the brain, neurons fire at different rates: some are faster, some are slower; and the rate of neuronal firing is what makes this fMRI show hot zones or cold zones. If the brain is firing fast, meaning higher frequency, then the fMRI shows overactivity. If the brain area is firing slowly, meaning lower frequency, then that functional MRI shows underactivity. With TMS, what we’re doing is sending a high frequency pulse, tuned to 10 hertz, and increasing the rate of firing of the underactive brain area. Our goal is to speed up that part of the brain (Siebner H et al, Clin Neurophysiol2022;140:59-97).

CPTR: And what happens to that brain area after treatment?

Dr. Ahmed: When a person is sitting in the TMS chair getting this high-frequency pulse stimulation, that underlying brain area has no choice but to fire at 10 hertz, which is what we want. But when the person is done with treatment and they walk away, that underlying brain area will do whatever it wants. The goal of treatment is to steadily increase the rate of firing for that brain area throughout treatment, a process that we call “entrainment,” and for this to persist post-treatment. We want the neurons to entrain to the high-frequency pulse.

CPTR: What makes a patient a good candidate for TMS treatment? 

Dr. Ahmed: The clinical trials that have been done with TMS have been in a population of folks who have major depressive disorder who haven’t responded to one, two, or more antidepressants. Among that population, the efficacy data is fairly strong in comparison to other treatments (Somani A and Kar SK, Gen Psychiatr 2019;32(4):e100074). But when it comes to knowing who will respond to TMS, the answer is, we don’t know. There is a functional MRI study that shows that there are certain neural circuitry that, when disrupted, do predispose patients to a better effect for TMS, but it’s not strong data. It’s nothing we can use to say “Hey, Person A is going to have a great response to TMS, but Person B will not.” Beyond that, there are no good demographic data, nor is there any clinical symptom phenotype/genotype type information that helps us determine who is a good candidate. 

CPTR: When we look diagnostically, the empirical research shows that TMS is highly effective for refractory depression, correct? Has it been studied for use in the treatment of other psychiatric disorders?

Dr. Ahmed: Oh, it has. I’ll tell you this, when TMS first came out for depression it was extremely exciting in our field, and researchers were testing it on everything: ADHD, autism, anything you can think of. The reason it was so easy to test on other psychiatric disorders was because of the safety profile. It’s a very safe treatment and so it’s easy to do these types of studies. It’s FDA approved, not just for major depressive disorder, but for obsessive-compulsive disorder, and also for nicotine use disorder, interestingly. There are clinical trials that have found effectiveness for generalized anxiety disorder, PTSD, even auditory hallucinations in schizophrenia (Cheng JL et al, World J Psychiatry 2023;13(9):607-619). 

CPTR: Do insurers cover TMS for these sorts of “off-label” uses?

Dr. Ahmed: While TMS is generally covered for FDA-approved uses if it’s being used off-label, it’s a guarantee that the insurance will not cover it. The typical cost of a full TMS treatment course is between $6,000 and $11,000.

CPTR: What do you think is essential for psychotherapists to know about TMS? 

Dr. Ahmed: One of the goals of TMS is to upregulate the activity of this dorsolateral prefrontal cortex, which is underactive in folks who have major depression. There is one more very important piece of the puzzle here. The dorsolateral prefrontal cortex is very highly connected to a deeper brain structure, called the subgenual anterior cingulate cortex (SGACC). The SGACC is more closely related to emotional production, whereas the dorsolateral prefrontal cortex is more associated with emotional regulation or emotional control. So in these FDG-PET studies that have looked at the brain pre-TMS and the brain post-TMS, what has been found is that when TMS is successful, meaning when patients get better, the dorsolateral prefrontal cortex is upregulated and the subgenual anterior cingulate cortex is downregulated (Baeken C et al, Brain Stimul 2015;8(4):808-815). There is a reciprocal relationship between the dorsolateral prefrontal cortex and the SGACC.

CPTR: What is the role of this brain region?

Dr Ahmed: The role of the dorsolateral prefrontal cortex is vast. If we just put the emotional aspect on the side for a second and look at the cognitive aspect of the dorsolateral prefrontal cortex, we find that it houses our executive function. Executive function is our ability to problem solve and abstract. And the dorsolateral prefrontal cortex is also associated with attentional control: our ability to focus and maintain focus. It also houses our working memory, which is like the RAM of the brain. For example, you would remember a phone number I just gave you in your working memory for a few seconds. But you would likely forget it not long after and if I asked you five minutes later what that phone number was, you would remember it. Because you weren’t trying to remember it; it was just in your working memory for a small period of time. So, the dorsolateral prefrontal cortex, what I’ll call the DLPFC, is a site of that as well.

CPTR: And from the emotional standpoint?

Dr. Ahmed: From an emotional standpoint, the DLPFC increases in activity when we’re using psychotherapeutic techniques to manage our emotional state. When we’re trying to restructure our cognitions and look within and understand why we’re feeling how we are feeling the DLPFC lights up. What I’ve found is that folks who undergo TMS can utilize psychotherapy more than usual. Maybe their psychotherapist has been telling the patient a strategy for months or years, but it doesn’t click until their DLPFC upregulates.

CPTR:  Do you know if there is any empirical research on combining TMS with various psychotherapies?

Dr. Ahmed: No, I don’t think there are any studies like that. But it does hold true in my clinical experience. 

CPTR: Can you tell us more about a usual course of treatment? 

Dr. Ahmed: TMS is done Monday through Friday in the office for a period of about 19 minutes over eight weeks. It’s very lengthy. Logistically, completing TMS is tough. 

CPTR:  What are some of the known side effects of TMS?

Dr. Ahmed: Headaches are the most common side effects, generally a scalp ache. Of course, the goal is to stimulate the underlying brain area, but we also end up stimulating all the tissue beneath the device, including all the tissues in the scalp. And every time the magnetic pulse fires, the scalp muscles contract, and so it can be uncomfortable. Nausea is also common. As I mentioned before, DLPFC has connections with the SGACC, which has very rich connections with the brainstem which houses the parasympathetic nervous system. So, by stimulating the SGACC, we stimulate the parasympathetic nervous system which starts in the brainstem and goes down to the stomach.

CPTR: How often do these side effects result in the patient dropping out of treatment?

Dr. Ahmed: Very rarely, in my experience probably less than 1% of the time.

CPTR: Why choose TMS over ECT or ketamine for a patient unresponsive to traditional antidepressants?

Dr. Ahmed: It’s a great question. Before TMS, all we had other than antidepressants was ECT. The problem is there’s a huge leap going from medications to ECT. It’s a very effective treatment, but it has a lot of potential side effects, is very invasive, so it’s not something I think every person with treatment-refractory depression should try. Although TMS is not as efficacious as ECT, it has much better tolerability, requires no anesthesia, has fewer side effects, and is also covered by insurance. And the effect holds for a long time. This has been studied quite a bit in the TMS research world. Once people have had a good effect from TMS their brain holds that good effect for a lengthy period. In the longest durability study, researchers found that if depression remitted with TMS at the one-year mark, there was a 70% chance that the depression would remain in remission (Dunner DL et al, J Clin Psychiatry 2014;75(12):1394-1401). I would say it’s fair to refer someone who has tried two antidepressants and hasn’t had success.

CPTR: Can you speak a little bit on some of the advantages TMS might have over ketamine?

Dr. Ahmed: The efficacy of ketamine and TMS are comparable (Mikellides G et al, Front Psychiatry 2022;12:784830). The difference between the two boils down to the maintenance treatment that's required for ketamine. A consistent finding, apart from the efficacy, is that ketamine doesn’t last very long; it’s rapidly acting, but the effect wears off after days or weeks. The FDA-approved version of ketamine (Spravato) (approved in 2019), requires maintenance, often indefinitely. I tend to think that TMS should be tried first because it has better durability, and if it’s ineffective, then maybe Spravato or ketamine should be the next option after that.

CPTR: Interesting. Well to wrap up, I’m wondering if you have any thoughts or where the world of TMS goes from here? What’s on the horizon in TMS research and clinically for those of you who practice this modality of treatment?

Dr. Ahmed: It’s a very exciting field and there are always new developments coming out. Since the FDA approval of the standard TMS protocol, there is now a deep TMS protocol that’s FDA approved that goes something like three times deeper into the brain, and the idea is that hey if we stimulate closer to that subgenual anterior cingulate cortex and downregulate it maybe we’ll get better effect. There are also some newer data that has come out in the last couple of years through the neuromodulation program at Stanford. They jammed an entire course of TMS into a one-week period, and instead of giving them the standard TMS they gave them something called “theta burst” which doesn’t deliver a 10-hertz treatment but delivers a 50-hertz treatment (Cole EJ et al, Am J Psychiatry 2022;179(2):132-141). More than 80% of the folks had remission. And the folks that they put into the study were extremely treatment refractory. It was unbelievable. So, there has been steady progress in the field of neuromodulation, and I think it’s going to be a massive component of psychiatry. 

CPTR: Thank you for your time, Dr. Ahmed.

References in order of appearance in this article

Siebner, H. R., Funke, K., Aberra, A. S., Antal, A., Bestmann, S., Chen, R., Classen, J., Davare, M., Di Lazzaro, V., Fox, P. T., Hallett, M., Karabanov, A. N., Kesselheim, J., Beck, M. M., Koch, G., Liebetanz, D., Meunier, S., Miniussi, C., Paulus, W., Peterchev, A. V., … Ugawa, Y. (2022). Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 140, 59–97. https://doi.org/10.1016/j.clinph.2022.04.022

Somani A, Kar SK. Efficacy of repetitive transcranial magnetic stimulation in treatment-resistant depression: the evidence thus far. Gen Psychiatr. 2019;32(4):e100074. Published 2019 Aug 12. doi:10.1136/gpsych-2019-100074.

Cheng JL, Tan C, Liu HY, Han DM, Liu ZC. Past, present, and future of deep transcranial magnetic stimulation: A review in psychiatric and neurological disorders. World J Psychiatry. 2023;13(9):607-619. Published 2023 Sep 19. doi:10.5498/wjp.v13.i9.607.

Baeken C, Marinazzo D, Everaert H, et al. The Impact of Accelerated HF-rTMS on the Subgenual Anterior Cingulate Cortex in Refractory Unipolar Major Depression: Insights From 18FDG PET Brain Imaging. Brain Stimul. 2015;8(4):808-815. doi:10.1016/j.brs.2015.01.415.

Dunner DL, Aaronson ST, Sackeim HA, et al. A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period. J Clin Psychiatry. 2014;75(12):1394-1401. doi:10.4088/JCP.13m08977

Mikellides G, Michael P, Psalta L, Schuhmann T, Sack AT. A Retrospective Naturalistic Study Comparing the Efficacy of Ketamine and Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression. Front Psychiatry. 2022;12:784830. Published 2022 Jan 13. doi:10.3389/fpsyt.2021.784830.

Cole EJ, Phillips AL, Bentzley BS, et al. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J Psychiatry. 2022;179(2):132-141). Doi:10.1176/appi.ajp.2021.20101429.