woman with glowing brain metaphor for tms for depression

New evidence identifies TMS-induced changes in brain function that help improve symptoms of depression.

TMS and Depression Treatment

In 2008, treatment for major depressive disorder took a major step forward.

That’s the year the Food and Drug Administration (FDA) approved the used of transcranial magnetic stimulation (TMS) for major depressive disorder (MDD). In 2013, the FDA approved TMS for treatment-resistant depression. Then, in 2013, the FDA approved TMS for the treatment of obsessive-compulsive disorder (OCD) and migraine headaches. Most recently, in 20202, the FDA approved TMS for treating tobacco/nicotine use disorder.

In addition, patients and providers around the U.S. report TMS helps relieve the symptoms of anxiety, post-traumatic stress disorder, and can reduce instances of suicidal ideation in patients with depressive disorders and anxiety disorders.

The approval of TMS for treatment-resistant depression was an important step forward because evidence shows that for one third of people diagnosed with major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression, traditional treatment with standard antidepressants and psychotherapy is not effective and does not lead to symptom relief or improved quality of life.

These FDA approvals tell us that TMS is a safe and effective treatment for a wide variety of mental health disorders. Research from early lab tests to the most recent clinical trials show TMS works by using electromagnetic pulses and precise targeting to stimulate brain areas associated with mood, emotion, and behavior.

To learn more about how TMS can help people with treatment-resistant depression (TRD), please read our TMS treatment page here:

Transcranial Magnetic Stimulation (TMS)

For information on how TMS can help people with bipolar disorder and other mental health challenges, please navigate to the blog section of our website and read these articles:

Can TMS Help People Who Have Bipolar Disorder?

What Can Neuroimaging Studies Tell Us About Treatment-Resistant Depression?

TMS is a unique treatment that leverages the latest technologies to relieve the symptoms of treatment-resistant depression. Before we share the results of a new study on the details about how TMS works, we’ll share some of the most recent data on the effectiveness of TMS for depression treatment.

The Evidence: TMS for Depression Treatment

Studies show that for people with treatment resistant depression (TRD), a treatment plan with TMS can:

  • Reduce symptoms in 50%-60% of patients
  • Lead to full remission of symptoms in 30%-40% of patients
  • Reduce symptoms of MDD and TRD for three months or longer

In a study of 100 patients who reported at least three unsuccessful attempts at depression treatment:

  • 51% experienced symptom reduction six weeks after treatment
  • 25% experienced full remission six weeks after treatment

Additional research shows that for people with bipolar I disorder (BD-I) II bipolar II disorder (BD-II), a treatment plan with TMS can:

The evidence is clear. TMS is a safe and effective approach for the treatment of depression, treatment-resistant depression, and other mental health and/or mood disorders that include depressive symptoms.

TMS: How it Works to Treat Depression

If you understand how MRI technology works, you know how TMS works. MRI stands for magnetic resonance imaging. It works when a specially designed machine emits electromagnetic pulses targeted at a particular body part or area. Those pulses bounce off the target area, and the MRI technology translates the returning pulses into an image of the target area.

TMS works the same way, except the machine directs electromagnetic pulses toward the specific areas of the brain related to the disorder being treated. That’s an oversimplification. But think about it like this: with TMS, the stimulation is the therapy.

The machine does not need to translate the returning waves to form an image, which is the next big difference between an MRI scan and treatment with TMS. The machines are much smaller than those used for MRI, and patients don’t need to lie down and slide part way or all the way into a big, loud piece of medical equipment.

Now we’re on the same page about how TMS works.

But why does it work?

The simple way to understand that question is what we say above. The stimulation is the treatment. Researchers understand and can track the enhanced activity in specific brain areas that occurs after a TMS session. However, enhanced activity doesn’t show precisely what’s happening. It shows that something is happening. What researchers want to know now is what that something is.

The study we’ll discuss today aims to do exactly that.

In the paper “Targeted Neurostimulation Reverses a Spatiotemporal Biomarker of Treatment-Resistant Depression” published in May 2023, researchers embarked on a close examination of what happens in the brain after TMS treatment. This paper not only identified one important phenomenon, but also discovered what a previously unrecognized biomarker for identifying depression.

Let’s look at that study now.

TMS, Brain Activity, and Depression Treatment

As we mention above, researchers, clinicians and patients all know TMS can relieve the symptoms of various treatment-resistant mental health disorders in a safe, quick, and effective manner. They know it works by stimulating neurons – i.e. brain cells – in areas of the brain associated with mood, emotion, and cognitive processing.

What they don’t know is why.

One theory is that TMS can alter the way information moves from one brain area to another. Here’s how Dr. Anish Mitra, a researcher on the study, describes the situation:

“The leading hypothesis has been that TMS could change the flow of neural activity in the brain. But to be honest, I was pretty skeptical. I wanted to test it.”

To test the hypothesis, Dr. Mitra and the research team chose a short-duration TMS protocol called Stanford Neuromodulation Therapy (SNT). Typical TMS treatment occurs over several weeks with follow-up sessions spread out over the following months. The SNT protocol condenses this timeline. Patients participate in ten sessions over five days. For Mitra and colleagues, this protocol was ideal, because it allowed them to collect and analyze their data and results in a timeline of several weeks rather than several months.

They paired this protocol with a technique called fMRI, or functional MRI, which creates real-time images of brain activity. For the purposes of this study, fMRI analysis allowed researchers to see the flow of information in the brain before, during, and after TMS session. That means they could not only identify that brain areas were stimulated, but which brain areas information in the brain was flowing to and from. This allowed them to confirm or deny the hypothesis that TMS alters the flow of information in the brain. It also allowed them to determine the direction of information flow, which has a direct impact on the subjective experience of symptoms associated with depression.

TMS, Depression, and Information Flow: How They Conducted the Study

With the appropriate protocols ready, the research team selected 33 patients diagnosed with treatment-resistant depression and divided them into two groups. One group of 23 patients received TMS treatment. Researchers called this the active-SNT group. The other group of ten patients received a sham/placebo treatment. Researchers called this the sham-SNT group. In addition, the research team used brain imaging information on 85 patients without TRD to compare results from the active-SNT and the sham-SNT group. They called this third group the healthy control group, or the HC group.

The team tested five hypotheses:

  1. Whether SNT changes information flow in the brain. This was the baseline hypothesis.
  2. Whether SNT-related changes improve depressive symptoms. This was the clinical hypothesis that relied on confirmation of the initial hypothesis.
  3. Whether information flow differs between healthy controls and people with TRD. The results around this hypothesis surprised researchers. We’ll elaborate below.
  4. Whether SNT restores/resets information flow in people with TRD.
  5. Whether baseline information flow patterns predicted response to SNT treatment.

After researchers conducted the protocols and analyzed the fMRI data, they found something they didn’t expect. This is the surprise we refer to above. They observed that in people without TRD, information flowed from a brain region called the anterior insula to a brain region called the anterior cingulate cortex. I 75 percent of the people with TRD, however, information flowed in the opposite direction. In those patients, the brain sent signals from the anterior cingulate cortex to the anterior insula.

Information Flow and Depression: Why It Matters

The anterior insula (AI) processes information from the body – heart rate, temperature, etc. – and sends it to the to the anterior cingulate cortex (ACC), which controls emotions. In a typical brain, the AI send signals the to ACC. The ACC interprets these signals and produces emotions. In other words, the AI offers a status report, and the ACC decides how we feel, based on that status report.

What surprised researchers was that in the case of people with TRD, the ACC sent signals related to emotion to the AI, rather than the other way around. That means that before receiving any input, the brain already determined an emotional state. The researchers also observed that the more severe the symptoms of depression, the larger the proportion of brain signals traveling from the ACC to the AI.

That confirmed hypothesis three, above.

Here’s how Dr. Mitra described this finding:

“What we saw is that who’s the sender and who’s the receiver in the relationship seems to really matter in terms of whether someone is depressed. It’s almost as if you’d already decided how you were going to feel, and then everything you were sensing was filtered through that. The mood has become primary.”

Any patient with depression can relate to that right away: the mood becomes primary, and subsumes and impacts everything else. With this information, the research team analyzed the rest of the data to confirm or deny their hypotheses.

Here’s what they found:

  • Hypothesis 1: Did SNT Change Brain Flow?
    • Answer: Yes. fMRI results confirmed TMS with the SNT protocol changed the flow of information between the AI and the ACC.
  • Hypothesis 2: Did SNT Change Depressive Symptoms?
    • Answer: Yes. Scores on the Montgomery-Asberg Depression Rating Scale (MADRS) improved significantly for patients in the active-SNT group, as compared to the sham-SNT group.
  • Hypothesis 3: Was Information Flow Different in Health Controls, Compared to People with TRD?
    • Answer: Yes. This is the finding we discussed above.
  • Hypothesis 4: Did SNT Reset/Restore Typical Information Flow?
    • Answer: Yes. After a week of treatment, researchers observed a return to the typical flow of information – AI to ACC – in patients with TRD.
  • Hypothesis 6: Did Baseline Information Flow Patterns Predict Treatment Response?
    • Answer: Yes. A higher proportion of atypical information flow predicted a more robust change in depressive symptoms.

We’ll elaborate on these results now.

How this Information Helps Clinicians and People with Depression

This study enhances our knowledge in three areas.

First, it clarifies a mechanism by which TMS improves the symptoms of depression in people diagnosed with treatment-resistant depression. The study shows that TMS can reverse the information flow between brain areas and restore atypical functioning to typical functioning and connects this change to symptom improvement – that’s new, important data.

Second, it identifies a biomarker – i.e., a physical signature – that’s present in people with severe depression. This is important because most mental health disorders don’t have clear biomarkers. For instance, to test for the flu or pneumonia, a laboratory can identify the presence of a viral or bacterial pathogen by specific physical signatures. This study reveals a physical signature that can help clinicians predict severity of depression and help fine-tune a treatment like TMS for maximum therapeutic effect.

Third, and finally, this information shows that advanced imaging and brain stimulation techniques can help move mental health treatment forward into the 21st century. The combination of targeted TMS and fMRI – technologies that are relatively new – can not only help researchers explore cutting-edge techniques, but also help clinicians apply these new techniques in real world situations and improve the lives of people with depression and other mental health disorders.