It is estimated that globally 121 million people suffer from clinical depression. Despite an extensive psychotherapeutic and pharmacological arsenal, many affected individuals continue to suffer while the burden on the health care system increases. Of the millions affected worldwide, 20% to 40% are resistant to pharmacological antidepressant treatments while another third show poor response.1 Many medications are associated with significant adverse effects (eg, weight gain, sexual dysfunction), and there is a recognized need for better treatment options for treatment-resistant depression.
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, nonconvulsive neurostimulation treatment. Approval of an rTMS device was granted by the FDA in October 2008. The approval was for 10 Hz stimulation of the left dorsolateral prefrontal cortex (DLPFC) as a treatment for major depression in patients who have not responded to only one antidepressant. rTMS has rather benign adverse effects—the most frequent are mild headache, nausea, and irritation at point of stimulation.2 The most serious adverse effect is the induction of a seizure, which is exceedingly rare, with an estimated incidence of less than 1 in 1000 patients.
Mechanism of action
Magnetism and electricity are intrinsically related to each other. Electrical currents generate magnetic fields (eg, magnetic resonance scanners), and conversely, magnetic fields elicit currents in conductors. rTMS takes advantage of this link and makes use of the electromagnetic induction phenomenon to elicit a focal current in brain tissue strong enough to trigger action potentials in neurons. And, it does so in a noninvasive fashion (ie, there is no need for a surgical intervention).
A coil made of an electrical conductor that is isolated by a plastic shell acts as the inductor. When pulses of current pass through the coil, a strong focal magnetic field is generated (on the order of 1.5 to 2 Tesla). This magnetic field crosses the skull and soft tissue unimpeded; the brain tissue acts as the conductor, and an electrical current is generated parallel to the current in the coil windings and in the opposite direction. The current induced is maximal at the focal point of the coil and diminishes with distance. It is sufficiently strong to cause neuronal polarization and depolarization in the volume lying 3 to 4 cm around the focal point. The entire procedure is carried out with no need for general anesthesia or prior procedural preparation (eg, intravenous line, heart rate or blood pressure monitoring), as opposed to other convulsive neurostimulation techniques, such as magnetic seizure therapy and electroconvulsive therapy.
A brief overview
Beginning in the 1980s, a series of positron emission tomography (PET) studies showed that glucose metabolism is reduced in a number of areas of the prefrontal cortex, including the DLPFC.3,4 Additional research using PET demonstrated that effective antidepressant treatment was correlated with reversing the hypoactivity in the prefrontal cortex.5,6 More recent studies using functional MRI (fMRI) and electroencephalographic recordings show that it is not only the DLPFC that changes its level of activation.7,8 A network of brain regions involved in cognitive control and emotion regulation, including the DLPFC, changes its activity in response to effective antidepressant treatment.
The large body of convergent evidence pointing at the DLPFC as a neuroanatomical location of interest in depression built a compelling and solid rationale for early studies using rTMS to target the DLPFC in depression treatment.9-11 Pilot studies then showed that rTMS to the left DLPFC was an effective treatment for a proportion of patients with major depressive episodes who had not responded to earlier antidepressant treatments. Indeed, a recent meta-analysis shows that rTMS is effective in 30% to 40% of individuals with treatment-resistant depression.12
Conventional rTMS protocols typically target the left DLPFC. The discharge frequency of stimulation (ie, the number of times the magnetic field is generated and the current induced on brain tissue) is usually at a frequency of 10 Hz; this high-frequency stimulation increases cortical excitability. Other protocols have targeted the right DLPFC using low-frequency stimulation at 1 Hz; this protocol decreases cortical excitability.
Dr Vila-Rodriguez is Clinical Assistant Professor in the department of psychiatry, Schizophrenia Program, The University of British Columbia, Vancouver. Dr Downar is the Head of the MRI-Guided rTMS Clinic, department of psychiatry, Toronto Western Hospital, and Assistant Professor in the department of psychiatry, University of Toronto, Toronto. Dr Blumberger is Assistant Professor in the department of psychiatry at the University of Toronto, Clinician Scientist at the Campbell Family Research Institute, and Medical Head of the Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto. Dr Vila-Rodriguez reports no conflicts of interest concerning the subject matter of this article. Dr Downar reports that he has received a travel stipend from Lundbeck. Dr Blumberger reports that he has received research support for an investigator-initiated study from Brainsway Ltd Equipment and support for an investigator-initiated study from Magventure, Inc.
1. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659.
2. Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009;120:2008-2039.
3. Baxter LR Jr, Schwartz JM, Phelps ME, et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry. 1989;46:243-250.
4. Drevets WC, Videen TO, Price JL, et al. A functional anatomical study of unipolar depression. J Neurosci. 1992;12:3628-3641.
5. Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12:527-544.
6. Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830-843.
7. Siegle GJ, Thompson W, Carter CS, et al. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61:198-209.
8. Ulrich G, Renfordt E, Frick K. The topographical distribution of alpha-activity in the resting EEG of endogenous-depressive inpatients with and without clinical response to pharmacotherapy. Pharmacopsychiatry. 1986;19:272-273.
9. George MS, Wassermann EM, Williams WA, et al. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995;6:1853-1856.
10. Pascual-Leone A, Rubio B, Pallardó F, Catalá MD. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. 1996;348:233-237.
11. Downar J, Daskalakis ZJ. New targets for rTMS in depression: a review of convergent evidence. Brain Stimul. 2013;6:231-240.
12. Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can J Psychiatry. 2008;53:621-631.
13. Isenberg K, Downs D, Pierce K, et al. Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment-resistant depressed patients. Ann Clin Psychiatry. 2005;17:153-159.
14. Fitzgerald PB, Hoy K, Daskalakis ZJ, Kulkarni J. A randomized trial of the anti-depressant effects of low- and high-frequency transcranial magnetic stimulation in treatment-resistant depression. Depress Anxiety. 2009;26:229-234.
15. Hill AJ. First occurrence of hippocampal spatial firing in a new environment. Exp Neurol. 1978;62:282-297.
16. Klimesch W, Doppelmayr M, Russegger H, Pachinger T. Theta band power in the human scalp EEG and the encoding of new information. Neuroreport. 1996;7:1235-1240.
17. Larson J, Wong D, Lynch G. Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res. 1986;368:347-350.
18. Staubli U, Lynch G. Stable hippocampal long-term potentiation elicited by ‘theta’ pattern stimulation. Brain Res. 1987;435:227-234.
19. Huang YZ, Rothwell JC. The effect of short-duration bursts of high-frequency, low-intensity transcranial magnetic stimulation on the human motor cortex. Clin Neurophysiol. 2004;115:1069-1075.
20. Huang YZ, Rothwell JC, Edwards MJ, Chen RS. Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human. Cereb Cortex. 2008;18:563-570.
21. Huang YZ, Rothwell JC, Lu CS, et al. The effect of continuous theta burst stimulation over premotor cortex on circuits in primary motor cortex and spinal cord. Clin Neurophysiol. 2009;120:796-801.
22. Chistyakov AV, Rubicsek O, Kaplan B, et al. Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. Int J Neuropsychopharmacol. 2010;13:387-393.
23. O’Reardon JP, Blumner KH, Peshek AD, et al. Long-term maintenance therapy for major depressive disorder with rTMS. J Clin Psychiatry. 2005;66:1524-1528.
24. Berlim MT, Van den Eynde F, Daskalakis ZJ. High-frequency repetitive transcranial magnetic stimulation accelerates and enhances the clinical response to antidepressants in major depression: a meta-analysis of randomized, double-blind, and sham-controlled trials. J Clin Psychiatry. 2013;74:e122-e129.
25. Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med. 2013 Mar 18; [Epub ahead of print].
26. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010;67:507-516.
27. O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208-1216.
28. Levkovitz Y, Harel EV, Roth Y, et al. Deep transcranial magnetic stimulation over the prefrontal cortex: evaluation of antidepressant and cognitive effects in depressive patients. Brain Stimul. 2009;2:188-200.