By some quirk of physics and as first described by the English scientist Michael Faraday in 1831, a changing electrical current produces a strong magnetic field. The idea of exploiting this to stimulate the brain was first proposed over 100 years ago although the technology to produce strong enough magnetic fields to stimulate the brain was not developed until the mid-1980s. These machines, first built in Sheffield in the UK, were not developed with any intent to treat disorders like depression but to explore nerve function, by activating the “muscle areas” of the brain and measuring the twitches produced.
However, relatively soon after TMS was invented, it was noted that if TMS pulses were applied repeatedly, they could change brain activity: this was observed as increases and decreases in excitability of the motor cortex. If pulses were repeated very quickly, one after another, usually between five to twenty times per second, they would transiently increase the activity of the area of the brain stimulated. As well as increasing brain activity, researchers found that they could do the opposite. If the pulses were applied much more slowly, usually about one pulse per second, the effect was to reduce, rather than increase brain activity. These two approaches, called high and low-frequency stimulation, were unprecedented tools to selectively ‘tune up and tune down’ areas of the brain and corresponding brain functions.
It did not take long before people started to explore the potential beneficial effects of TMS. Depression was the first cab off the rank. This was partially historical: there was an established practice of using ECT in treating depression, so doctors were used to thinking about its treatment from a brain stimulation perspective. It was also a matter of timing. As TMS was becoming available, positron emission tomography (PET) scans were starting to show that the left prefrontal cortex was relatively consistently underactive in patients with depression. Based on these early imaging studies, it was proposed that high-frequency or “activating” TMS could be applied to this left frontal region in the treatment of patients with depression.
Of note, this is one of the few times in the field of psychiatry where a treatment has been developed with a specific hypothesis based on research evidence. This has certainly not been the case with most types of medications used in psychiatry, the precursors of which have mostly been discovered by chance.
Several groups tested this idea, first at Harvard University and the National Institutes for Mental Health in Washington DC, conducting small clinical trials in the mid-1990s. The first studies were in small groups of patients and in retrospect used a low dose of stimulation but both suggested that TMS might have beneficial effects in depressed patients.
These results generated great excitement and a flourishing of research around the world during the late 1990s, including multiple placebo-controlled trials. Most of these initial studies showed positive benefits. However, not all did. In the early 2000s, there were a couple of ‘negative’ trials published: showing no difference between real and fake treatment. This was not surprising as many of these were very small (had few patients) or used questionable methods of placebo treatment (some might actually have been really stimulating the brain when they thought they were doing nothing).
Despite these limitations, the negative studies resulted in a considerable waning of enthusiasm for TMS at the time. It was in this context that I first started doing TMS research on depression. I was told by many, many people in those initial years that it didn’t or wouldn’t work. I spoke to researchers who had given up because they thought the data showed it wasn’t going to be helpful. This seemed just silly to me: the studies done to date just did not include enough patients to say one way or the other. And we really, really needed new treatments for depression: it was just too early to jump off this horse.
Starting the first clinical trial we did in this atmosphere, I was perhaps somewhat sceptical about what we would find. We finished and published our first clinical trial in 2002, one of the very first to include more than 50 patients. And we saw really promising results: clear benefits of 2 different types of TMS compared to placebo. Perhaps equally as important, were the stories of patients who experienced dramatic improvements in their mood. We included patients in this first study who had been depressed for many years, in some for decades. And in some, TMS was the first thing that gave them relief. And for many, relief meant a complete resolution of the depression and their ability to get back on with their life.
These experiences really sparked my enthusiasm, and I am pleased to say, I heard from lots of researchers around the world that the results of the study rekindled new enthusiasm for TMS in many of them, in some directly leading to the conduct of new trials.
Things progressed relatively quickly from there. By the mid-2000 a large multisite trial was underway, sponsored by a company called Neuronetics Ltd. They had some protected IP based on their TMS coil and were able to attract sufficient investment to conduct a study across multiple hospitals in North America and in Australia. We participated in and recruited patients for this study, even though we had some questions about aspects of the protocol. It was by far the best chance that the type of data would be collected that would be required to achieve regulatory approval. Despite some limitations of the study and its results, this was the case and by 2008 the Neuronetics TMS device was on the market in the US and the era of clinical use of TMS had begun in earnest.
A second multisite trial, conducted independently of industry, confirming the results of the first study, was published in 2010. Since then multiple TMS devices have become clinically available and clinical services have spread around the world. We developed our first clinical program, integrating research and the provision of clinical TMS delivery, in the mid-2000s at the Victoria Clinic, an inpatient hospital, in Melbourne. We expanded this program to a number of other hospitals around the country.
The program allowed us to provide access to TMS and conduct an important series of large clinical trials. TMS was taken up widely in Australia in the private hospital sector but I was always concerned that this was an inefficient and limiting location for clinical delivery. The vast majority of patients requiring TMS don’t require inpatient admission but this was the only way that patients could access treatment for many years. It was for this reason, that I enthusiastically co-founded TMS Clinics Australia, the precursor of the Monarch Mental Health Group, with Dr Ted Cassidy. With a mission to ensure that a much broader range of patients could access TMS.
I also spent a good part of the 2010s writing submissions to the Medicare Services Advisory Committee in the Federal Health Department which eventually resulted in Medicare funding of TMS by the end of the decade. The Medicare funding rules are not perfect but they are certainly increasing access to TMS and this was a fantastic step forward.