History of TMS for Treatment of Depression

The concept of using magnetic to stimulate human brain and other parts of body in attempt to treat diseases can be tracked back to more than 100 years ago but the effectiveness was often not be approved by scientific studies. The first modern Transcranial Magnetic Stimulation (TMS) device was introduced in 1985 by Anthony Barker and colleagues. The physics behind this technique was originally discovered by Michael Faraday in 1881, who was able to create a magnetic field by running electricity through a coil. The changing or alternating magnetic field can also affect conductors in its vicinity, such as another metal coil conductor or neurons in the brain. In TMS, when applying the magnetic generated by a coil to the head, the brain will be permeated quite easily by the Magnetic Field and will affect the neurons. When the magnetic field intensified or changed quick enough, it affects the neurons by depolarizing them and making them release the neurotransmitters that regulate brain functions. 

In mid-1900's researchers from the field of Psychiatry started to study the effect of rTMS (repetitive Transcranial Magnetic Stimulation) in treatment of depression (George et al, 1995; Pascual-Leone et al., 1996). More and more studies published thereafter demonstrated that rTMS can be used therapeutically for a long lasting effect in a variety of mental disorders besides the widely studied depression. More than 10 years later, about 90 clinical trials done and several meta-analyses suggested a moderate effect size in treatment of major depression. The first phase III, randomized, sham-controlled multi-site study that used rTMS in treatment-resistant major depression of 301 patients was conducted and led to US FDA approval of this new technique in clinical treatment of depression (O'Reardon et al, 2007). It showed substantial improvement of the patients’ mood (14.2% remission rate in active treatment group vs 5.5% in sham) with a effect size at least comparable to a medication but much better safety or side effect profile. However, the result is questioned by many reviewers due to the marginal p values and one unsatisfying p value of the statistics on the primary outcome measure when all qualified participants are included. After long period of review, the first rTMS equipment was finally cleared by FDA and was announced officially in 2008 with an indication: for patient who failed one medication. Eventually, another large trial funded by NIMH was published with a similar result (14.1% remission rate in active treatment vs 5.1% in sham) and satisfying statistics (p=.02) (George et al, 2010). This is a good starting point for rTMS use in the management of Treatment Resistant Depression, a devastating brain disease lack of effective and safe treatment, but the outcome number does not appear so attractive to many people. Meanwhile, another version of TMS, called deep rTMS or dTMS with a newly designed coil (H-coil) targeting on deeper brain structures was under study. 

The phase III trial on dTMS treatment of major depression was launched in 2009 and Dr Xia's research team at UC Davis enrolled the first patient for this trial. The study was finished in 2012. The result revealed an exciting improvement: remission rate of 32.6 in active deep TMS (vs 14.6 sham treatment). The statistic p value also reach another convincing level (P=.005). Number needed to treat was improved from around 9-11 down to about 6 with a still excellent safety/side effect profile. The sample of participants includes all kinds of highly treatment resistant patients who failed 2 or more medications in current index depression episode. This time the FDA review committee approve the clinical use of dTMS very quickly, which led to the manufacturer unprepared for launching its marketing procedure until almost half year later of July 2013 for first group of clinic receiving their equipment. The deep TMS indications include patients who failed any number of medications or intolerable to medications.

After this TMS study was completed, the TMS technique become more accepted. More and more clinics start to accept it for treatment of depression for not only the convince treatment effects demonstrated by the large phase III trials, but also the advantages of the TMS over medications and ECT. Unlike medications, TMS does not have systemic effects such as weight gain, sexual dysfunction, nausea, tremors, dry mouth, diarrhea, headaches, constipation, sweating, sleepiness or anxiety. It also does not generate any cognitive impairment that was observed in ECT treatment such as memory impairment and no anesthesia or muscle relaxant medication are needed. The patient is awake and alert through the procedure and can resume routine activities right after the treatment is done. To date there has been no long-term side effects of TMS. Comparing to most MRI machines in clinical settings, it use a lower intensity and approved to be safe.