Transcranial Magnetic Stimulation
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For other uses, see TMS (disambiguation).
Transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a noninvasive method to cause depolarization or hyperpolarization in the neurons of the brain. TMS uses electromagnetic induction to induce weak electric currents using a rapidly changing magnetic field; this can cause activity in specific or general parts of the brain with minimal discomfort, allowing the functioning and interconnections of the brain to be studied. A variant of TMS, repetitive transcranial magnetic stimulation (rTMS), has been tested as a treatment tool for various neurological and psychiatric disorders including migraines, strokes, Parkinson’s disease, dystonia, tinnitus, depression and auditory hallucinations.
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 in Sheffield, England. Its earliest application demonstrated conduction of nerve impulses from the motor cortex to the spinal cord, stimulating muscle contractions. The use of magnets rather than a direct electric current to the brain reduced the discomfort of the procedure and research and allowed mapping of the cerebral cortex and its connections.
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 although it is widely believed to reflect changes in synaptic efficacy akin to long-term potentiation (LTP) and long-term depression (LTD).
Although TMS is often regarded as safe, the greatest acute risk of TMS is the rare occurrence of induced seizures and syncope. At least 17 cases of TMS-related seizure have been reported in the literature, with at least seven reported before the publication of safety guidelines in 1998, and more than nine reported afterwards. The seizures have been associated with 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 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 which increases with the stimulator intensity that can affect hearing with sufficient exposure, particularly relevant for rTMS (hearing protection may be used to prevent this),
rTMS in the presence of incompatible EEG 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.
TMS can be used clinically to measure activity and function of specific brain circuits in humans. The most robust and widely-accepted use is in measuring the connection between the primary motor cortex and a muscle to evaluate damage from strokes, spinal cord injuries, multiple sclerosis and motor neuron disease. TMS has been suggested as a means of assessing short-interval intracortical inhibition (SICI) which measures the internal pathways of the motor cortex but this use has not yet been validated.
Studies of the use of TMS and rTMS to treat neurological and psychiatric conditions have 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 recent meta-analysis of 34 studies comparing rTMS to sham treatment showed an effect size of 0.55. 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 (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.
Other areas of research include the rehabilitation of aphasia and motor disability after stroke, tinnitus, Parkinson’s disease and the negative symptoms of schizophrenia. TMS has failed to show effectiveness for the treatment of brain death, coma, and other persistent vegetative states.
It is difficult to establish a convincing form of “sham” TMS to test for placebo effects during controlled trials 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 cerebral glucose metabolism and MEPs, which may confound results. This problem is exacerbated when using subjective measures of improvement. Depending on the research question asked and the experimental design, matching this discomfort to distinguish true effects from placebo can be an important and challenging issue.
A recent multicenter trial of rTMS in depression used a “sham” placebo treatment that appeared to mimic the sound and scalp stimulation associated with active TMS 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.
FDA actions and responses
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) (see: Medical device#Classification) “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.