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Transcranial magnetic stimulation: using a law of physics to treat psychopathology Gary M. Hasey, MD, MSc J Psychiatry Neurosci 1999;24(2):97-101 Department of Psychiatry, McMaster University, Hamilton, Ont. Correspondence to: Dr. Gary M. Hasey, Clinical Director, Mood Disorders Program, Hamilton Psychiatric Hospital, 100 West 5th St., Hamilton ON L8N 3K7; fax 905 575-6014 Medical subject headings: depressive disorder; electroconvulsive therapy; electromagnetic fields; prefrontal cortex; stimulation, electric Submitted Dec. 1, 1998 Accepted Jan. 4, 1999 © 1999 Canadian Medical Association Contents Introduction Harnessing magnetic fields TMS as a treatment modality Comparing TMS with ECT Side effects and safety Unknown mechanism Conclusion References Introduction Galvani and Volta demonstrated in the 1790s that electric currents could influence the activity of muscle and nerve. However, this knowledge was not used effectively in psychiatry until 1938, when Cerletti and Bini1 first described electroconvulsive therapy (ECT). More than 60 years later, ECT remains one of the most powerful antidepressant treatments. Apart from the addition of anesthesia and some relatively minor technical refinements, the procedure is essentially the same as Cerletti and Bini described it. This could be seen as scientific inertia and lack of progress, or probably more accurately, as an indication of the fundamental soundness of the strategy of using electromagnetic energy to modulate neuronal activity. Despite its often-remarkable efficacy, ECT remains a crude technique, analogous to sculpting rock with explosive charges. With some skill and attention to energy output, the end result may be very acceptable, but control is difficult and unwanted effects are common. We have now been given a newer and more easily controlled tool: transcranial magnetic stimulation (TMS). For the first time, we have a noninvasive way to change the firing rate or electrochemical excitability of neurons in relatively small regions of the cerebral cortex. [Contents] Harnessing magnetic fields The notion that magnetic fields can be used to modulate brain activity is not new. D'Arsonval2 in 1896 and Thompson3 in 1910 built large electromagnetic stimulators, but they could not produce magnetic fields intense enough with the available technology. They succeeded only in activating retinal neurons to create "phosphenes" -- perceived light flashes -- in volunteers. It was not until 1985 that Barker4 developed an electromagnetic field generator with sufficient power to activate cortical neurons. Barker's TMS device consisted of a stimulation coil made up of wire loops encased in insulating material and connected to a capacitor capable of passing a large electrical current through the coil over a very brief time interval. This design is the basis of all modern devices. As the current flows through the coil, a short-lived but very powerful (1 to 2 Tesla) magnetic field is generated around the coil. When the coil of Barker's device was placed over the scalp overlying the motor cortex and the current turned on, sufficient voltage was induced within cortical neurons to result in depolarization, causing observable involuntary movement of the finger and hand. The physical principle involved is known as Faraday induction. When an electric current is passed through a coil, a magnetic field is generated. If another coil or length of conductive material such as a nerve fibre is exposed to a changing magnetic field, a secondary electrical field is induced within the exposed coil or fibre. The size of the current induced depends on the strength and rate of change of the magnetic field and on the number of loops in the secondary coil or, in the case of TMS, the anatomical conformation of underlying nerve fibres. Neurons with bent or curved axonal processes, passing at right angles to the lines of force of the magnetic field, are most easily activated. The size and shape of the magnetic field are readily determined. However, the precise brain structures stimulated, and the resulting physiological effect of magnetic stimulation, cannot be inferred directly from available mathematical models because the head and brain are irregularly shaped, inhomogeneous volume conductors, and because the spatial orientation and anatomical configuration of underlying nerve fibres are variable. Nevertheless, advances in coil design have led to stimulators capable of activating a small enough region of the cortex to allow mapping of cortical functioning with a degree of precision rivalling that achieved using direct electrode stimulation of the brain. Coupled with other devices such as the electromyograph, Barker's stimulator has become an important diagnostic tool in clinical neurology, as well as an investigational tool for studying regional cortical involvement in processes as diverse as motor functioning, vision and Braille reading. Application of TMS for treatment of neuropsychiatric conditions is a more recent development. The main technological innovations since Barker's first design are the repetitive stimulator and the figure-of-8 coil. The repetitive stimulator (rTMS) is capable of delivering not only single magnetic pulses, but also a very rapid series or "train" of magnetic pulses (e.g., 5 to 30 pulses per second or Hz). This attribute may be critical to the optimal use of TMS. A train of pulses appears to be capable of producing more profound changes in neuronal activity than those produced by a single pulse. As well, the nature of the neuronal response to TMS may ultimately prove to be dependent upon stimulation frequency. The figure-of-8 coil is also important because it creates a much more focused magnetic field than the original round or teardrop-shaped coils. This permits greater stimulation precision, as a smaller area of cortex is exposed to the most intense part of the magnetic field. We are now equipped with a very powerful technology. Commercially available devices can produce magnetic fields of intensity greatly exceeding the threshold for depolarization of neurons, at least in the motor cortex, and advances in coil design permit focused stimulation of small regions of cerebral cortex. The most immediate challenge for users in psychiatry is to determine the optimal stimulation parameters and anatomical stimulation site for different neuropsychiatric conditions. In the process of working through these issues we will undoubtedly learn a great deal about the neurophysiological underpinnings of various neuropsychiatric diseases. [Contents] TMS as a treatment modality The earliest investigations of the potential of TMS as a therapeutic agent in psychiatric disorders involved the use of single-pulse stimulators and round coils. Hoflich et al5 treated 2 patients with major depressive psychosis refractory to pharmacotherapy with 10 days of TMS using an open design. Somewhat later, they treated 15 patients with major depressive disorder (MDD) with either high- or low-intensity TMS or sham TMS.6 Although some patients showed improvement, the results were generally disappointing and not statistically significant. However, in both studies TMS was given as a series of single electromagnetic pulses (0.25 to 0.50 Hz) delivered with a circular coil over the vertex. We have since learned that repetitive stimulation using a figure-of-8 coil and prefrontal cortex stimulation sites may show considerably better results. Although Conca et al7 were able to show improvement in patients with depression treated with single pulses (delivered at 6-second intervals), they stimulated several sites, including prefrontal areas, and all subjects received antidepressant medications concurrently. George et al8 were the first to identify the left prefrontal cortex as an important stimulation site in patients with depression. In an open trial, they treated 6 patients with depression that was very resistent to pharmacotherapy with rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC). This site was chosen on the grounds that depression was associated with hypoperfusion of this region. They employed a repetitive stimulator set to deliver 20 Hz pulses through a figure-of-8 coil. Four of the 6 patients showed improvement, and 1 had a complete remission. The importance of the prefrontal stimulation site was confirmed by Pasqual-Leone et al9 in the first controlled, fully blind study of rTMS. They treated 17 patients with depressive psychosis refractory to pharmacotherapy with genuine rTMS (10 Hz, figure-of-8 coil) or sham stimulation administered to the left DLPFC, right DLPFC or vertex in random sequence. There was a highly significant difference between sham and genuine rTMS, and significantly more improvement of depression after treatment delivered to the left DLPFC compared with other stimulation sites. Additional support for the involvement of the prefrontal cortex in mood regulation comes from studies in healthy control subjects. Pasqual-Leone et al,10 and George et al11 separately demonstrated in volunteer subjects that rTMS administered to the left prefrontal region increased sadness scores, while right prefrontal rTMS increased happiness scores. Stimulation of other brain regions had no significant effect. Interestingly, these effects are the opposite of those seen in patients with depression, for whom high-frequency rTMS has antidepressant effects only when administered to the left side. In keeping with these "lateralized" findings, Grisaru et al12 demonstrated, in 16 patients, that rTMS (20 Hz) administered to the right DLPFC has a greater antimanic effect than rTMS to the left DLPFC. The duration of the improvement of mood after successful treatment with rTMS has not yet been clearly established, but appears to be at least in the order of weeks to months. There is some evidence that longer remission of depression can be obtained with higher rTMS stimulus energies (J.M. Tormos et al: unpublished data). In all likelihood, relapse rates for depression similar to those seen with ECT will be revealed over future studies, and maintenance TMS or antidepressant drug prophylaxis will be necessary. Mood stabilizers may also play a role, even in unipolar depression. Tormos et al,13 for example, reported that patients treated with rTMS for major depression had a longer-lasting improvement when the rTMS was given together with the mood stabilizer and anticonvulsant gabapentin. [Contents] Comparing TMS with ECT ECT and TMS are the only techniques that use electrical energy to induce neuropsychiatric change, and this naturally invites comparison of the two. In animals, rTMS can produce behavioural and biological effects that are qualitatively similar though slightly less robust than those seen after electroconvulsive shock (ECS). These effects include enhanced apomorphine-induced stereotypy, reduced immobility in the Porsolt swim test, increased seizure threshold,14 increased brain dopamine and serotonin levels15 and ß-adrenoreceptor down-regulation.16 To date, there is only one open trial comparing ECT with rTMS in patients with depression. In this study, Grunhaus et al17 treated 26 subjects with severe major depression with either left prefrontal rTMS (10 Hz) or right unilateral ECT. Patients in the ECT group who did not show improvement by the seventh ECT were switched to bilateral ECT. As expected, the researchers observed clinically and statistically significant improvement in both the groups receiving ECT and rTMS. There were no significant differences in antidepressant response between the groups, except that sleep improved more completely among the patients in the ECT group. [Contents] Side effects and safety The roughly equivalent efficacy of ECT and TMS is all the more striking given the apparently benign side-effect profile and procedural simplicity of TMS. TMS may be slightly uncomfortable, but is certainly not painful, and anesthesia is not required. Patients remain alert throughout the procedure, can walk and function immediately afterward and do not require any special post-treatment supervision. There appears to be no significant cognitive impairment associated with the treatment. In some patients rTMS causes what may be muscle-tension headache, which can persist for some hours after the end of the stimulation session. Special precautions must be taken to prevent hearing damage. Deformation of the coil with the passage of the electrical current results in a deceptively unimpressive "click"; however, the frequency is one at which the human ear is especially vulnerable to acoustic injury, so foam earplugs should be worn both by the subject and operator during rTMS. There is no evidence of neuronal histotoxicity resulting from TMS, but there is a theoretical risk of heat injury in poorly perfused areas such as cysts or infarcts, and patients with such lesions should be excluded, as should all patients with intracranial metal objects such as surgical clips. The functioning of cardiac pacemakers can be altered by TMS; hence, patients with pacemakers should not be treated. The most serious adverse effect appears to be seizures during treatment. To my knowledge, fewer than 10 seizures have been reported among the thousands of patients who have received this treatment. The already very low risk of seizure can be further reduced by excluding patients with a personal or family history of seizure disorder, and by keeping the stimulation parameters within currently recommended safety guidelines. Although TMS has been used safely together with mood stabilizers, neuroleptics and many antidepressants, one patient had a seizure during TMS after taking a combination of amitriptyline and haloperidol without the investigators' knowledge.18 "Kindling" -- a process by which repeated subconvulsive stimuli eventually lower the seizure threshold so that seizures occur without stimulation -- is also a theoretical possibility. However, kindling has not been observed in humans. In animals, low-frequency electrical stimulation has been reported to raise the seizure threshold or "quench" seizures kindled by highfrequency stimulation of the amygdala.19 It is possible that low-frequency rTMS may have similar anticonvulsant effects. Admittedly, the long-term biological effects of TMS are not yet well understood. Concerns have been raised about the possible carcinogenic effect of long-term exposure to magnetic fields generated by electrical cables or appliances in the workplace or home,20 but the evidence for this is weak and the nature of the exposure very different from that of TMS. The period of exposure during TMS is very brief, the field strength high and the frequency usually 20 Hz or less. The exposure to the fields induced by power lines and electrical equipment is of many years' duration, the field strength weak and the frequency generally 50 to 60 Hz. [Contents] Unknown mechanism The mechanism by which TMS alters neuropsychiatric functioning is unknown. However, there is some evidence that high-frequency rTMS (10 to 20 Hz) may increase cortical excitability, while low-frequency TMS (1 Hz) may reduce cortical excitability. Speer et al21 demonstrated that high-frequency rTMS (20 Hz) applied to the left DLPFC increases cerebral blood flow over this region in patients with depression, while low-frequency rTMS (1 Hz) produces the opposite effect. In accordance with this indirect evidence, Chen et al22 found that low-frequency rTMS (0.9 Hz) reduced the excitability of the motor cortex for at least 15 minutes after the end of rTMS in healthy volunteers, while Tergau et al23 observed enhanced cortical excitability after TMS trains with frequencies of 10 Hz or more in their subjects. This apparent capacity to either increase or decrease cortical excitability and neuronal metabolic activity may be central to the efficacy of TMS treatment for mood disorders and other neuropsychiatric diseases. As an example, PasqualLeone24 has demonstrated that depression may be alleviated by either highfrequency rTMS over the left DLPFC or low-frequency rTMS over the right DLPFC. We may have, for the first time, a way to selectively and noninvasively "tune" the cerebral cortex to correct or compensate for the neuronal dysfunction that produces psychopathology or neurological disease. TMS is currently being tested for therapeutic effects in other psychiatric disorders, with encouraging preliminary results. Greenberg et al25 have reported that compulsive urges were improved for 8 hours in patients with obsessivecompulsive disorder after right prefrontal rTMS. However, in a short case series, a patient with panic disorder and another with generalized anxiety disorder showed increased anxiety after right prefrontal rTMS.26 Other groups using a single session of 30 lowfrequency TMS treatments have observed transient improvement in patients with post-traumatic stress disorder27 and schizophrenia.28 The open design, small sample size and limited number of stimulation sites tested in these studies make interpretation difficult; however, TMS may find major applications outside of affective disorders. [Contents] Conclusion Where will TMS take us in the future? Further experimentation with stimulation parameters and sites using current technology will lead to greater therapeutic efficacy for mood disorders and to delineation of other neuropsychiatric conditions that may respond to TMS. Better understanding of the combined use of pharmacotherapy with TMS may allow more rapid and longer-lasting improvement in psychiatric conditions and in neurological diseases such as epilepsy and Parkinson's disease. More powerful magnetic-field generators, new coil conformations and arrays of several coils used simultaneously will allow stimulation of currently inaccessible regions, such as the inferior orbital cortex, or deeper structures, such as the basal ganglia. In the more distant future, miniaturization may lead to more portable or even implantable magnetic neuromodulators. Whatever the direction empirical research into this technology takes us, our understanding of both pathophysiology and the functioning of the healthy brain will inevitably grow. Send a letter to the editor Envoyez une lettre à la rédaction References 1. 2. Cerletti U, Bini L. L'Elettroshock. Arch Gen Neurol Psichiatr Psicoanal 1938;19:266. d'Arsonval A. Dispositifs pour la mesure des courants alternatifs de toutes frequences. C R Soc Biol (Paris) 1896;3:450-7. 3. Thompson SP. A physiological effect of an alternating magnetic field. Proc R Soc Lond B Biol Sci 1910;82:396-8. 4. Barker AT, Freeston IL, Jalinous R, Jarratt JA. Non-invasive stimulation of motor pathways within the brain using time-varying magnetic fields. Electroencephalogr Clin Neurophysiol 1985;61:S245. 5. Hoflich G, Kasper S, Hufnagel A, Ruhrmann S, Moller HJ. Application of transcranial magnetic stimulation in treatment of drug-resistant major depression: a report of two cases. Hum Psychopharmacol 1993;8:361-5. 6. Kolbinger HM, Hoflich G, Hufnagel A, Moller HJ, Kasper S. Transcranial magnetic stimulation (TMS) in the treatment of major depression: a pilot study. Hum Psychopharmacol 1995;10: 305-10. 7. Conca A, Koppi S, Konig P, Swoboda E, Krecke N. Transcranial magnetic stimulation: a novel antidepressant strategy? Neuropsychobiology 1996;34:204-7. 8. George MS, Wassermann EM, Williams WA, Callahan A, Ketter T, Basser P, et al. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport 1995;6:1853-6. 9. Pasqual-Leone A, Rubio B, Pallardo F, Catala MD. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug resistant depression. Lancet 1996;348:233-7. 10. Pasqual-Leone A, Catala MD. Lateralized effect of rapid rate transcranial magnetic stimulation of the prefrontal cortex on mood. Neurology 1996;46:499-502. 11. George MS, Wassermann EM, Williams WA, Steppel J, Pasqual-Leone A, Basser P, et al. Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation (rTMS) of the prefrontal cortex. J Neuropsychiatry Clin Neurosci 1996;8:172-80. 12. Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH. Transcranial magnetic stimulation in mania: a controlled study. Am J Psychiatry 1998;155:1608-10. 13. Tormos JM, Pasqual-Leone A, Catala MD, Keenan JP, Bachna K. Gabapentin prolongs the antidepressant effects of rTMS (abstract). Biol Psychiatry 1998,43(85 Suppl):22S. 14. Fleishmann A, Prolov K, Abarbanel J, Belmaker RH. The effect of transcranial magnetic stimulation of rat brain on behavioral models of depression. Brain Res 1995;699:130-2. 15. Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. Transcranial magnetic stimulation induces alterations in brain monoamines. J Neural Transm 1997;104:191-7. 16. Zyss T, Gorka Z, Kowalska M, Vetulani J. Preliminary comparison of behavioral and biochemical effects of chronic transcranial magnetic stimulation and electroconvulsive shock in the rat. Biol Psychiatry 1997;42:920-4. 17. Grunhaus L, Dannon P, Schreiber S. Effects of transcranial magnetic stimulation on severe depression (abstract). Biol Psychiatry 1998;43(85 Suppl):76S. 18. Pasqual-Leone A, Wassermann EM. Repetitive transcranial magentic stimulation: applications and safety considerations. In: Nilsonn J, Panizza M, Grandorf F, editors. Advances in occupational medicine & rehabilitation. Pavia (Italy): Fondazione Salvatore Maugeri Edizioni; 1996. p. 105-16. 19. Weiss SRB, Li X, Rosen JB, Li H, Heynen T, Post R. Quenching: inhibition of development and expression of amygdala kindled seizures with low frequency stimulation. Neuroreport 1995;6: 21716. 20. Loomis DP, Savitz DA, Ananth CV. Breast cancer mortality among female electrical workers in the United States. J Am Cancer Inst 1994;86:921-5. 21. Speer AM, Kimbrell TA, Dunn RT, Osuch EA, Frye M, Willis MW, et al. Differential changes in rCBF with one versus 20 Hz rTMS in depressed patients. In: The New Research Proceedings of the Annual Meeting of the American Psychiatric Association. 1998 May 30June 4; Toronto. p. 82. 22. Chen R, Classen J, Gerloff C, Celnik P, Wasserman EM, Hallett M, Cohen LG. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 1997; 48:13981403. 23. Tergau F, Tormos JM, Paulus W. Effects of repetitive transcranial magnetic stimulation on cortcospinal and cortico-cortical excitability (abstract). Neurology 1997;48:A107. 24. Pasqual-Leone A. Why does rTMS have an antidepressant effect ? Differences with ECT. Biol Psychiatry 1998;43:76S-77S. 25. Greenberg B, George M, Martin J, Benjamin J, Schlaepfer T, Altemus M, et al. Effect of prefrontal repetitive transcranial stimulation on obsessive-compulsive disorder: a preliminary study. Am J Psychiatry 1997;154:867-9. 26. Greenberg B, McCann U, Benjamin J, Murphy D. Repetitive transcranial magnetic stimulation as probe in anxiety disorders: theoretical considerations and case reports. CNS Spectrums 1997;2:47-52. 27. Grisaru N, Amir M, Cohen H, Kaplan Z. Effect of transcranial magnetic stimulation in post traumatic stress disorder: a preliminary study. Biol Psychiatry 1998;44:52-5. 28. Geller V, Grisaru N, Abarbanel JM, Lemberg T, Belmaker RH. Slow magnetic stimulation of prefrontal cortex in depression and schizophrenia. Prog Neuropharmacol Behav Psychiatr 1997; 21:105-10.