# Transcranial magnetic stimulation

Template:Lead rewrite Template:Infobox interventions Transcranial magnetic stimulation (TMS) is a noninvasive method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or "coil" is placed near the head of the person receiving the treatment.[1]:3 The coil produces small electrical currents in the region of the brain just under the coil via electromagnetic induction. The coil is connected to a pulse generator, or stimulator, that delivers electrical current to the coil.[2]

TMS is used diagnostically to measure the connection between the brain and a muscle to evaluate damage from stroke, multiple sclerosis, amyotrophic lateral sclerosis, movement disorders, motor neuron disease and injuries and other disorders affecting the facial and other cranial nerves and the spinal cord.[3]

TMS was approved by the FDA for use in migraine[4] and treatment-resistant major depressive disorder.[5]

Clinical evidence to date shows that TMS is useful for neuropathic pain (a condition for which evidence-based medicine fails to treat a significant number of people with the condition)[6] and treatment-resistant major depressive disorder.[6][7] Clinical evidence shows that TMS may be useful for negative symptoms of schizophrenia and loss of function caused by stroke.[6] As of 2014, all other potential uses have only possible or no efficacy.[6]

The greatest risks of TMS are the rare occurrence of syncope (fainting) and even less commonly, induced seizures.[8] Other adverse effects of TMS include discomfort or pain, transient induction of hypomania, transient cognitive changes, transient hearing loss, transient impairment of working memory, and induced currents in electrical circuits in implanted devices.[8]

## Medical uses

The use of TMS can be divided into diagnostic and therapeutic uses.

### Diagnosis

TMS can be used clinically to measure activity and function of specific brain circuits in humans.[3] The most robust and widely accepted use is in measuring the connection between the primary motor cortex and a muscle to evaluate damage from stroke, multiple sclerosis, amyotrophic lateral sclerosis, movement disorders, motor neuron disease and injuries and other disorders affecting the facial and other cranial nerves and the spinal cord.[3][9][10][11] 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.[12]

### Treatment

For neuropathic pain, a condition for which evidence-based medicine fails to treat a significant number of people with the condition, high-frequency (HF) rTMS of the brain region corresponding to the part of the body in pain, is effective.[6]

For treatment-resistant major depressive disorder, HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) is effective and low-frequency (LF) rTMS of the right DLPFC has probably efficacy.[6][7] The American Psychiatric Association,[13]:46 the Canadian Network for Mood and Anxiety Disorders,[14] and the Royal Australia and New Zealand College of Psychiatrists have endorsed rTMS for trMDD.[15]

For negative symptoms of schizophrenia, HF-rTMS of the left DLPFC has probable efficacy.[6]

For loss of function caused by stroke LF-rTMS of the corresponding brain region has probable efficacy.[6]

As of 2014, all other potential uses have only possible or no efficacy; TMS has failed to show effectiveness for the treatment of brain death, coma, and other persistent vegetative states.[6][16][17]

Although TMS is generally regarded as safe, risks increase for therapeutic rTMS compared to single or paired TMS for diagnostic purposes. In the field of therapeutic TMS, risks increase with higher frequencies.[8]

The greatest risk is the rare occurrence of syncope (fainting) and even less commonly, induced seizures.[8][18]

Other adverse effects of TMS include discomfort or pain, transient induction of hypomania, transient cognitive changes, transient hearing loss, transient impairment of working memory, and induced currents in electrical circuits in implanted devices.[8]

## Devices and procedure

During a transcranial magnetic stimulation (TMS) procedure, a magnetic field generator, or "coil" is placed near the head of the person receiving the treatment.[1]:3 The coil produces small electrical currents in the region of the brain just under the coil via electromagnetic induction. The coil is positioned by finding anatomical landmarks on the skull including, but not limited to, the inion or the nasion.[19] The coil is connected to a pulse generator, or stimulator, that delivers electrical current to the coil.[2]

## Society and culture

### Regulatory approvals

#### Navigated TMS

Nexstim obtained 510(k) FDA clearance of Navigated Brain Stimulation for the assessment of the primary motor cortex for pre-procedural planning in December 2009.[20]

Nexstim obtained FDA 510K clearance for NexSpeech navigated brain stimulation device for neurosurgical planning in June 2011.[21]

#### Depression

Neuronetics obtained FDA 510K clearance to market its NeuroStar System for use in adults with treatment-resistant major depressive disorder (December 2008).[5]

#### Migraine

eNeura Therapeutics obtained classification of Cenera System for use to treat migraine headache as a Class II medical device under the "de novo pathway"[22] in December 2013.[4]

### Health insurance considerations

#### United States

##### Commercial health insurance

In 2013, 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 for the first time.[23] In contrast, UnitedHealthcare issued a medical policy for TMS in 2013 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.[24] Other commercial insurance plans whose 2013 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.[25]

##### Medicare

There is no national policy for Medicare coverage of TMS in the United States. Policies vary according to local coverage determinations (LCDs) that Medicare administrative contractors (MACs) for the Centers for Medicare and Medicaid Services (CMS) make for geographical areas over which they have jurisdiction. CMS presently has ten to fifteen MAC jurisdictions that each cover several U.S. states.[26]

LCDs for individual MAC jurisdictions can change over time. For example:

• In early 2012, the efforts of TMS treatment advocates resulted in the establishment by a MAC with jurisdiction over New England of the first Medicare coverage policy for TMS in the United States.[27] However, a new MAC for the same jurisdiction subsequently determined that Medicare would not cover services for TMS performed in New England on or after October 25, 2013.[28]
• In August 2012, the MAC whose jurisdiction covered Arkansas, Louisiana, Mississippi, Colorado, Texas, Oklahoma and New Mexico determined that, based on limitations in the published literature there was insufficient evidence to cover the treatment,[29] but the same MAC subsequently determined that Medicare would cover TMS for the treatment of depression for services performed within the MAC's jurisdiction on or after December 5, 2013,[30]

CMS maintains a searchable database that enables users to find current Medicare LCDs for TMS for individual U.S. states.[32]

#### United Kingdom's National Health Service

The United Kingdom's National Institute for Health and Care Excellence (NICE) issues guidance to the National Health Service (NHS) in England, Wales, Scotland and Northern Ireland. NICE guidance does not cover whether or not the NHS should fund a procedure. Local NHS bodies (primary care trusts and hospital trusts) make decisions about funding after considering the clinical effectiveness of the procedure and whether the procedure represents value for money for the NHS.[33]

NICE evaluated TMS for severe depression (IPG 242) in 2007, and subsequently considered TMS for reassessment in January 2011 but did not change its evaluation.[34] The Institute found that TMS is safe, but there is insufficient evidence for its efficacy.[34]

In January 2014, NICE reported the results of an evaluation of TMS for treating and preventing migraine (IPG 477). NICE found that short-term TMS is safe but there is insufficient evidence to evaluate safety for long-term and frequent uses. It found that evidence on the efficacy of TMS for the treatment of migraine is limited in quantity, that evidence for the prevention of migraine is limited in both quality and quantity.[35]

## Technical information

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.[36]

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.[37] 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.[38]

### Mechanism of action

From the Biot–Savart law

${\displaystyle \mathbf {B} ={\frac {\mu _{0}}{4\pi }}I\int _{C}{\frac {d\mathbf {l} \times \mathbf {\hat {r}} }{r^{2}}}}$

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.[39] 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 as explained by the Maxwell-Faraday equation,

${\displaystyle \nabla \times \mathbf {E} =-{\frac {\partial \mathbf {B} }{\partial t}}}$ .

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.[39]

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.[40]
• 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).[41]

MRI images, recorded during TMS of the motor cortex of the brain, have been found to match very closely with PET produced by voluntary movements of the hand muscles innervated by TMS, to 5–22 mm of accuracy.[42] The localisation of motor areas with TMS has also been seen to correlate closely to MEG[43] and also fMRI.[44]

### Coil types

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.[45]

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[46]
• 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 produce a focused, localized response and are relatively non-focal.[8]

## History

Early attempts at stimulation of the brain using a magnetic field included those, in 1910, of Silvanus P. Thompson in London.[47] The principle of inductive brain stimulation with eddy currents has been noted since the 20th century{{ safesubst:#invoke:Unsubst||date=__DATE__ |\$B= {{#invoke:Category handler|main}}{{#invoke:Category handler|main}}[citation needed] }}. The first successful TMS study was performed in 1985 by Anthony Barker and his colleagues at the Royal Hallamshire Hospital in Sheffield, England.[48] 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[49] 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.

## Research

Areas of research include the rehabilitation of aphasia and motor disability after stroke,[10][11][6][8][50] tinnitus,[6][51] anxiety disorders,[6] obsessive-compulsive disorder,[6] amyotrophic lateral sclerosis,[6] multiple sclerosis,[6] epilepsy,[6] Alzheimer's disease,[6] Parkinson's disease,[52]schizophrenia,[6] substance abuse,[6] addiction,[6][53] and posttraumatic stress disorder (PTSD).[6][54]

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.[6][8] "Sham" TMS manipulations can affect cerebral glucose metabolism and MEPs, which may confound results.[55] This problem is exacerbated when using subjective measures of improvement.[8] Placebo responses in trials of rTMS in major depression are negatively associated with refractoriness to treatment, vary among studies and can influence results.[56] 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.[6][8]

## References

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