Early attempts at stimulation of the brain using a magnetic field included those, in 1910, of Silvanus P. Thompson in London. The principle of inductive brain stimulation with eddy currents has been noted since the 20th century. The first successful TMS study was performed in 1985 by Anthony Barker and his colleagues at the Royal Hallamshire Hospital in Sheffield, England. Its earliest application demonstrated conduction of nerve impulses from the motor cortex to the spinal cord, stimulating muscle contractions in the hand. As compared to the previous method of transcranial stimulation proposed by Merton and Morton in 1980 in which direct electrical current was applied to the scalp, the use of electromagnets greatly reduced the discomfort of the procedure, and allowed mapping of the cerebral cortex and its connections.
it has been shown that a current through a wire generates a magnetic field around that wire. Transcranial magnetic stimulation is achieved by quickly discharging current from a large capacitor into a coil to produce pulsed magnetic fields of 1-10 mT. By directing the magnetic field pulse at a targeted area of the brain, one can either depolarize or hyperpolarize neurons in the brain. The magnetic flux density pulse generated by the current pulse through the coil causes an electric field due to the Maxwell-Faraday equation,
This electric field causes a change in the transmembrane current of the neuron, which leads to the depolarization or hyperpolarization of the neuron and the firing of an action potential.
Effects on the brain
The exact details of how TMS functions are still being explored. The effects of TMS can be divided into two types depending on the mode of stimulation:
Single or paired pulse TMS causes neurons in the neocortex under the site of stimulation to depolarize and discharge an action potential. If used in the primary motor cortex, it produces muscle activity referred to as a motor evoked potential (MEP) which can be recorded on electromyography. If used on the occipital cortex, 'phosphenes' (flashes of light) might be perceived by the subject. In most other areas of the cortex, the participant does not consciously experience any effect, but his or her behaviour may be slightly altered (e.g., slower reaction time on a cognitive task), or changes in brain activity may be detected using sensing equipment.
Repetitive TMS produces longer-lasting effects which persist past the initial period of stimulation. rTMS can increase or decrease the excitability of the corticospinal tract depending on the intensity of stimulation, coil orientation, and frequency. The mechanism of these effects is not clear, though it is widely believed to reflect changes in synaptic efficacy akin to long-term potentiation (LTP) and long-term depression (LTD).
In 1996, a study was done by Wassermann et al. using TMS to stimulate areas in the motor cortex of the brain to move a finger. The stimulated areas were imaged with an MRI for the reference image. The subjects then were asked to move the same finger in the same way that it was moved by TMS, and PET images were obtained to map the corresponding activity in the brain. The TMS-induced MRI images matched very closely with the PET images, within 5–22 mm of accuracy. TMS has also been seen to correlate closely to MEG and also fMRI.
TMS is generally regarded as safe, although seizures have been reported in some cases. There have been 16 reports of TMS-related seizures (as of 2009), with seven reported before the publication of safety guidelines in 1998, and nine reported afterwards. The seizures have been associated with both single-pulse and rTMS. Reports have stated that in at least some cases, predisposing factors (medication, brain lesions or genetic susceptibility) may have contributed to the seizure. A review of nine seizures associated with rTMS that had been reported after 1998 stated that four seizures were within the safety parameters, four were outside of those parameters, and one had occurred in a healthy volunteer with no predisposing factors. A 2009 international consensus statement on TMS that contained this review concluded that based on the number of studies, subjects, and patients involved with TMS research, the risk of seizure with rTMS is considered very low.
Besides seizures, other risks include syncope (fainting), minor pains such as headache or local discomfort, minor cognitive changes, and psychiatric symptoms (particularly a low risk of mania in depressed patients). Though other side effects are thought to be possibly associated with TMS (alterations to the endocrine system, altered neurotransmitter, and immune system activity) they are considered investigational and lacking substantive proof.
Other adverse effects of TMS are:
Discomfort or pain from the stimulation of the scalp and associated nerves and muscles on the overlying skin; this is more common with rTMS than single pulse TMS.
Rapid deformation of the TMS coil produces a loud clicking sound that increases with the stimulation intensity and can affect hearing with sufficient exposure, which is particularly relevant for rTMS (hearing protection may be used to prevent this).
rTMS in the presence of EEG-incompatible electrodes can result in electrode heating and, in severe cases, skin burns. Non-metallic electrodes are used if concurrent EEG data is required.
The uses of TMS and rTMS can be divided into diagnostic and therapeutic uses.
Studies of the use of TMS and rTMS to treat many neurological and psychiatric conditions have generally shown only modest effects with little confirmation of results. However, publications reporting the results of reviews and statistical meta-analyses of earlier investigations have stated that rTMS appeared to be effective in the treatment of certain types of major depression under certain specific conditions. rTMS devices are marketed for the treatment of such disorders in Canada, Australia, New Zealand, the European Union, Israel and the United States.
A meta-analysis of 34 studies comparing rTMS to sham treatment for the acute treatment of depression showed an effect size of 0.55 (p<.001). This is comparable to commonly reported effect sizes of pharmacotherapeutic strategies for treatment of depression in the range of 0.17-0.46. However, that same meta-analysis found that rTMS was significantly worse than electroconvulsive therapy (ECT) (effect size = -0.47), although side effects were significantly better with rTMS. An analysis of one of the studies included in the meta-analysis showed that one extra remission from depression occurs for every 3 patients given electroconvulsive therapy rather than rTMS (number needed to treat 2.36). There is evidence that rTMS can temporarily reduce chronic pain and change pain-related brain and nerve activity, and TMS has been used to predict the success of surgically implanted electrical brain stimulation for the treatment of pain.
It is difficult to establish a convincing form of "sham" TMS to test for placebo effects during controlledtrials in conscious individuals, due to the neck pain, headache and twitching in the scalp or upper face associated with the intervention. "Sham" TMS manipulations can affect cerebralglucose metabolism and MEPs, which may confound results. This problem is exacerbated when using subjective measures of improvement. Placebo responses in trials of rTMS in major depression are negatively associated with refractoriness to treatment, vary among studies and can influence results. Depending on the research question asked and the experimental design, matching the discomfort of rTMS to distinguish true effects from placebo can be an important and challenging issue.
One multicenter trial of rTMS in depression used an active "sham" placebo treatment that appeared to mimic the sound and scalp stimulation associated with active TMS treatment. The investigators reported that the patients and clinical raters were unable to guess the treatment better than chance, suggesting that the sham placebo adequately blinded these people to treatment. The investigators concluded: "Although the treatment effect was statistically significant on a clinically meaningful variable (remission), the overall number of remitters and responders was less than one would like with a treatment that requires daily intervention for 3 weeks or more, even with a benign adverse effect profile". However, a review of the trial's report has questioned the adequacy of the placebo, noting that treaters were able to guess whether patients were receiving treatment with active or sham TMS, better than chance. In this regard, the trial's report stated that the confidence ratings for the treaters' guesses were low.
In January 2007, an advisory panel of the United States Food and Drug Administration (FDA) did not recommend clearance for marketing of an rTMS device, stating that the device appeared to be reasonably safe but had failed to demonstrate efficacy in a study of people with major depression who had not benefitted from prior adequate treatment with oral antidepressants during their current major depressive episode. The panel agreed that "unblinding was greater in the active group, and considering the magnitude of the effect size, it may have influenced the study results." However, the FDA determined in December 2008 that the rTMS device was sufficiently similar to existing devices that did not require a premarket approval application and allowed the device to be marketed in accordance with Section 510(k) of the Federal Food, Drug, and Cosmetic Act for "the treatment of Major Depressive Disorder in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode". The user manual for the device warns that effectiveness has not been established in patients with major depressive disorder who have failed to achieve satisfactory improvement from zero and from two or more antidepressant medications in the current episode and that the device has not been studied in patients who have had no prior antidepressant medication.
In July 2011, the FDA published a final rule in the Federal Register that classified the rTMS system into Class II (special controls) "in order to provide a reasonable assurance of safety and effectiveness of these devices". The rule identified the rTMS system as "an external device that delivers transcranial pulsed magnetic fields of sufficient magnitude to induce neural action potentials in the prefrontal cortex to treat the symptoms of major depressive disorder without inducing seizure in patients who have failed at least one antidepressant medication and are currently not on any antidepressant therapy". An FDA guidance document issued in conjunction with the final rule describes the special controls that support the classification of the rTMS system into Class II.
Response to FDA decision
Soon after the FDA cleared the device, several members of Public Citizen stated in a letter to the editor of the medical journal Neuropsychopharmacology that the FDA seemed to have based its decision on a post-hoc analysis that did not establish the effectiveness of rTMS for the treatment of depression. The writers of the letter expressed their concern that patients would be diverted from therapies such as antidepressant medications that have an established history of effectiveness.
Health insurance considerations
Commercial health insurance
In July 2011, the Technology Evaluation Center (TEC) of the Blue Cross Blue Shield Association, in cooperation with the Kaiser Foundation Health Plan and the Southern California Permanente Medical Group, determined that TMS for the treatment of depression did not meet the TEC's criteria, which assess whether a technology improves health outcomes such as length of life, quality of life and functional ability. The TEC's report stated that "the meta-analyses and recent clinical trials of TMS generally show statistically significant effects on depression outcomes at the end of the TMS treatment period. However, there is a lack of rigorous evaluation beyond the treatment period", which was, with a few exceptions, one to four weeks. The Blue Cross Blue Shield Association's medical advisory panel concluded that "the available evidence does not permit conclusions regarding the effect of TMS on health outcomes or compared with alternatives.”
In 2012, several commercial health insurance plans in the United States, including Anthem, Health Net, and Blue Cross Blue Shield of Nebraska and of Rhode Island, covered TMS for the treatment of depression. In contrast, UnitedHealthcare issued a medical policy for TMS in 2012 that stated there is insufficient evidence that the procedure is beneficial for health outcomes in patients with depression. UnitedHealthcare noted that methodological concerns raised about the scientific evidence studying TMS for depression include small sample size, lack of a validated sham comparison in randomized controlled studies, and variable uses of outcome measures. Other commercial insurance plans whose 2012 medical coverage policies stated that the role of TMS in the treatment of depression and other disorders had not been clearly established or remained investigational included Aetna, Cigna and Regence.
... the evidence is insufficient to determine rTMS improves health outcomes in the Medicare or general population. ... The contractor considers repetitive transcranial magnetic stimulation (rTMS) not medically necessary when used for its FDA-approved indication and for all off-label uses.
Current evidence suggests that there are no major safety concerns associated with transcranial magnetic stimulation (TMS) for severe depression. There is uncertainty about the procedure's clinical efficacy, which may depend on higher intensity, greater frequency, bilateral application and/or longer treatment durations than have appeared in the evidence to date. TMS should therefore be performed only in research studies designed to investigate these factors.
American Medical Association category codes
In 2011, the American Medical Association established three Category I CPT® Codes to be used for the reporting and billing of therapeutic repetitive transcranial magnetic stimulation treatment services. The three codes effective January 1, 2012 are:
90867 – Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management
90868 – Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent delivery and management, per session
90869 – Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent motor threshold re-determination with delivery and management
TMS - Butterfly Coils
TMS uses electromagnetic induction to generate an electric current across the scalp and skull without physical contact. A plastic-enclosed coil of wire is held next to the skull and when activated, produces a magnetic field oriented orthogonal to the plane of the coil. The magnetic field passes unimpeded through the skin and skull, inducing an oppositely directed current in the brain that activates nearby nerve cells in much the same way as currents applied directly to the cortical surface.
The path of this current is difficult to model because the brain is irregularly shaped and electricity and magnetism are not conducted uniformly throughout its tissues. The magnetic field is about the same strength as an MRI, and the pulse generally reaches no more than 5 centimeters into the brain unless using the deep transcranial magnetic stimulation variant of TMS. Deep TMS can reach up to 6 cm into the brain to stimulate deeper layers of the motor cortex, such as that which controls leg motion.
The design of transcranial magnetic stimulation coils used in either treatment or diagnostic/experimental studies may differ in a variety of ways. These differences should be considered in the interpretation of any study result, and the type of coil used should be specified in the study methods for any published reports.
The most important considerations include:
the type of material used to construct the core of the coil
the geometry of the coil configuration
the biophysical characteristics of the pulse produced by the coil.
With regard to coil composition, the core material may be either a magnetically inert substrate (i.e., the so-called ‘air-core’ coil design), or possess a solid, ferromagnetically active material (i.e., the so-called ‘solid-core’ design). Solid core coil design result in a more efficient transfer of electrical energy into a magnetic field, with a substantially reduced amount of energy dissipated as heat, and so can be operated under more aggressive duty cycles often mandated in therapeutic protocols, without treatment interruption due to heat accumulation, or the use of an accessory method of cooling the coil during operation. Varying the geometric shape of the coil itself may also result in variations in the focality, shape, and depth of cortical penetration of the magnetic field. Differences in the coil substance as well as the electronic operation of the power supply to the coil may also result in variations in the biophysical characteristics of the resulting magnetic pulse (e.g., width or duration of the magnetic field pulse). All of these features should be considered when comparing results obtained from different studies, with respect to both safety and efficacy.
A number of different types of coils exist, each of which produce different magnetic field patterns. Some examples:
round coil: the original type of TMS coil
figure-eight coil (i.e., butterfly coil): results in a more focal pattern of activation
double-cone coil: conforms to shape of head, useful for deeper stimulation
four-leaf coil: for focal stimulation of peripheral nerves
H-coil: for deep transcranial magnetic stimulation
Design variations in the shape of the TMS coils allow much deeper penetration of the brain than the standard depth of 1.5-2.5 cm. Circular crown coils, Hesed (or H-core) coils, double cone coils, and other experimental variations can induce excitation or inhibition of neurons deeper in the brain including activation of motor neurons for the cerebellum, legs and pelvic floor. Though able to penetrate deeper in the brain, they are less able to produced a focused, localized response and are relatively non-focal.
^Fitzgerald, P; Fountain, S; Daskalakis, Z (2006). "A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition". Clinical Neurophysiology117 (12): 2584–2596. doi:10.1016/j.clinph.2006.06.712. PMID16890483.edit
^ abcWassermann, E. M.; Wang, B.; Zeffiro, T. A.; Sadato, N.; Pascual-Leone, A.; Toro, C.; Hallett, M. (1996). "Locating the Motor Cortex on the MRI with Transcranial Magnetic Stimulation and PET". NeuroImage3 (1): 1–9. doi:10.1006/nimg.1996.0001. PMID9345470.edit
^T. Morioka, T. Yamamoto, A. Mizushima, S. Tombimatsu, H. Shigeto, K. Hasuo, S. Nishio, K. Fujii and M. Fukui. Comparison of magnetoencephalography, functional MRI, and motor evoked potentials in the localization of the sensory-motor cortex. Neurol. Res., vol. 17, no. 5, pp. 361-367. 1995
^Terao, Y.; Ugawa, Y.; Sakai, K.; Miyauchi, S.; Fukuda, H.; Sasaki, Y.; Takino, R.; Hanajima, R.; Furubayashi, T.; püTz, B.; Kanazawa, I. (1998). "Localizing the site of magnetic brain stimulation by functional MRI". Experimental Brain Research121 (2): 145. doi:10.1007/s002210050446.edit
^ abcdefghiRossi, S; Hallett, M; Rossini, PM; Pascual-Leone, A; Safety of TMS Consensus Group (2009). "Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research". Clinical Neurophysiology120 (12): 2008–2039. doi:10.1016/j.clinph.2009.08.016. PMID19833552.edit
^ abcWassermann, EM (1998). "Risk and safety of repetitive transcranial magnetic stimulation: Report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996". Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section108: 1–9. doi:10.1016/S0168-5597(97)00096-8. PMID9474057.edit
^Roth, BJ; Pascual-Leone, A; Cohen, LG; Hallett, M (1992). "The heating of metal electrodes during rapid-rate magnetic stimulation: A possible safety hazard". Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section85 (2): 116. doi:10.1016/0168-5597(92)90077-O. PMID1373364.edit
^ abGroppa, S.; Oliviero, A.; Eisen, A.; Quartarone, A.; Cohen, L. G.; Mall, V.; Kaelin-Lang, A.; Mima, T.; Rossi, S.; Thickbroom, G. W.; Rossini, P. M.; Ziemann, U.; Valls-Solé, J.; Siebner, H. R. (2012). "A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee". Clinical Neurophysiology123 (5): 858–882. doi:10.1016/j.clinph.2012.01.010. PMID22349304.edit
^ abDimyan, MA; Cohen, LG (2009). "Contribution of Transcranial Magnetic Stimulation to the Understanding of Functional Recovery Mechanisms After Stroke". Neurorehabilitation and Neural Repair24 (2): 125–135. doi:10.1177/1545968309345270. PMC2945387. PMID19767591.edit
^ abNowak, D; Bösl, K; Podubeckà, J; Carey, J (2010). "Noninvasive brain stimulation and motor recovery after stroke". Restorative Neurology and Neuroscience28 (4): 531–544. doi:10.3233/RNN-2010-0552. PMID20714076.edit
^Kujirai, T.; Caramia, M. D.; Rothwell, J. C.; Day, B. L.; Thompson, P. D.; Ferbert, A.; Wroe, S.; Asselman, P.; Marsden, C. D. (1993). "Corticocortical inhibition in human motor cortex". The Journal of physiology471: 501–519. PMC1143973. PMID8120818. edit
^ abcdSlotema, C. W.; Blom, J. D.; Hoek, H. W.; Sommer, I. E. C. (2010). "Should We Expand the Toolbox of Psychiatric Treatment Methods to Include Repetitive Transcranial Magnetic Stimulation (rTMS)?". The Journal of Clinical Psychiatry71 (7): 873–884. doi:10.4088/JCP.08m04872gre. PMID20361902. edit
^Bersani, F. S.; Minichino, F. S.; Capra, E.; Bonanno, R.; Pannese, C.; Salviati, M.; Chiaie, D.; Biondi, M. (2012). "ECT, rTMS, and deepTMS in pharmacoresistant drug-free patients with unipolar depression: A comparative review". Neuropsychiatric Disease and Treatment8: 55–64. doi:10.2147/NDT.S27025. PMC3280107. PMID22347797. edit
^Eranti, S.; Mogg, A.; Pluck, G.; Landau, S.; Purvis, R.; Brown, R. G.; Howard, R.; Knapp, M.; Philpot, M.; Rabe-Hesketh, S.; Romeo, R.; Rothwell, J.; Edwards, D.; McLoughlin, D. M. (2007). "A Randomized, Controlled Trial with 6-Month Follow-Up of Repetitive Transcranial Magnetic Stimulation and Electroconvulsive Therapy for Severe Depression". American Journal of Psychiatry164 (1): 73–81. doi:10.1176/appi.ajp.164.1.73. PMID17202547.edit
^(1) Martin, PI; Naeser, MA; Ho, M; Treglia, E; Kaplan, E; Baker, EH; Pascual-Leone, A (2009). "Research with Transcranial Magnetic Stimulation in the Treatment of Aphasia". Current Neurology and Neuroscience Reports9 (6): 451–458. doi:10.1007/s11910-009-0067-9. PMC2887285. PMID19818232. edit (2) Corti, M; Patten, C; Triggs, W (2012). "Repetitive Transcranial Magnetic Stimulation of Motor Cortex after Stroke". American Journal of Physical Medicine & Rehabilitation91 (3): 254–270. doi:10.1097/PHM.0b013e318228bf0c. PMID22042336.edit
^Kleinjung, T; Vielsmeier, V; Landgrebe, M; Hajak, G; Langguth, B (2008). "Transcranial magnetic stimulation: a new diagnostic and therapeutic tool for tinnitus patients". The international tinnitus journal14 (2): 112–8. PMID19205161. edit
^Lefaucheur, JP (2009). "Treatment of Parkinson’s disease by cortical stimulation". Expert Review of Neurotherapeutics9 (12): 1755–1771. doi:10.1586/ern.09.132. PMID19951135.edit
^Steeves, T.; McKinlay, B. D.; Gorman, D.; Billinghurst, L.; Day, L.; Carroll, A.; Dion, Y.; Doja, A.; Luscombe, S.; Sandor, P.; Pringsheim, T. (2012). "Canadian guidelines for the evidence-based treatment of tic disorders: Behavioural therapy, deep brain stimulation, and transcranial magnetic stimulation". Canadian journal of psychiatry. Revue canadienne de psychiatrie57 (3): 144–151. PMID22398000. edit
^Dlabač-De Lange, JJ; Knegtering, R; Aleman, A (2010). "Repetitive Transcranial Magnetic Stimulation for Negative Symptoms of Schizophrenia". The Journal of Clinical Psychiatry71 (4): 411. doi:10.4088/JCP.08r04808yel. PMID20361909.edit
^Lapitska, N; Gosseries, O; Delvaux, V; Overgaard, M; Nielsen, F; Maertens De Noordhout, A; Moonen, G; Laureys, S (2009). "Transcranial magnetic stimulation in disorders of consciousness". Reviews in the neurosciences20 (3-4): 235–50. PMID20157993. edit
^Brunoni, A. R.; Lopes, M.; Kaptchuk, T. J.; Fregni, F. (2009). "Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis". In Hashimoto, Kenji. PLoS ONE4 (3): e4824. doi:10.1371/journal.pone.0004824. PMC2653635. PMID19293925. edit
^ abcGeorge, M. S.; Lisanby, S. H.; Avery, D.; McDonald, W. M.; Durkalski, V.; Pavlicova, M.; Anderson, B.; Nahas, Z.; Bulow, P.; Zarkowski, P.; Holtzheimer Pe, 3.; Schwartz, T.; Sackeim, H. A. (2010). "Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder: A Sham-Controlled Randomized Trial". Archives of General Psychiatry67 (5): 507–516. doi:10.1001/archgenpsychiatry.2010.46. PMID20439832.edit
^(1) Zangen, A.; Roth, Y.; Voller, B.; Hallett, M. (2005). "Transcranial magnetic stimulation of deep brain regions: Evidence for efficacy of the H-Coil". Clinical Neurophysiology116 (4): 775–779. doi:10.1016/j.clinph.2004.11.008. PMID15792886.edit (2) Huang, YZ; Sommer, M; Thickbroom, G; Hamada, M; Pascual-Leonne, A; Paulus, W; Classen, J; Peterchev, AV; Zangen, A; Ugawa, Y (2009). "Consensus: New methodologies for brain stimulation". Brain Stimulation2 (1): 2–13. doi:10.1016/j.brs.2008.09.007. PMID20633398. edit
^Riehl M (2008). "TMS Stimulator Design". In Wassermann EM, Epstein CM, Ziemann U, Walsh V, Paus T, Lisanby SH. Oxford Handbook of Transcranial Stimulation. Oxford: Oxford University Press. pp. 13–23, 25–32. ISBN0-19-856892-4.
^Roth, BJ; MacCabee, PJ; Eberle, LP; Amassian, VE; Hallett, M; Cadwell, J; Anselmi, GD; Tatarian, GT (1994). "In vitro evaluation of a 4-leaf coil design for magnetic stimulation of peripheral nerve". Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section93: 68. doi:10.1016/0168-5597(94)90093-0. PMID7511524.edit