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Transcranial magnetic stimulation (TMS) is a noninvasive method to excite neurons in the brain: weak electric currents are induced in the tissue by rapidly changing magnetic fields (electromagnetic induction). This way, brain activity can be triggered with minimal discomfort, and the functionality of the circuitry and connectivity of the brain can be studied.

Repetitive transcranial magnetic stimulation is known as rTMS and can produce longer lasting changes. Numerous small-scale pilot studies have shown it could be a treatment tool for various neurological conditions (e.g. migraine, stroke, Parkinsons Disease, dystonia, tinnitus) and psychiatric conditions (e.g. major depression, auditory hallucinations).

Contents 1 Background and history 2 How TMS affects the brain 3 TMS and rTMS techniques in research 4 Risks of TMS and rTMS 5 Clinical uses of TMS and rTMS 5.1 TMS for diagnostic purposes 5.2 TMS for therapeutic purposes 6 TMS equipment 7 FDA approval 8 Technical information on TMS 8.1 TMS coil types 9 References 10 See also 11 External links

[edit] Background and history

The principle of inductive brain stimulation with eddy currents has been noted since the 19th century. The first successful TMS study was performed in 1985 by Anthony Barker et al.^[1] in Sheffield, England. Its earliest application was in the demonstration of conduction of nerve impulses from the motor cortex to the spinal cord. This had been done with transcranial electrical stimulation a few years earlier, but use of this technique was limited by severe discomfort. By stimulating different points of the cerebral cortex and recording responses, e.g., from muscles, one may obtain maps of functional brain areas. By measuring functional imaging (e.g. MRI) or EEG, information may be obtained about the cortex (its reaction to TMS) and about area-to-area connections.

Pioneers in the use of TMS in neuroscience research include Anthony Barker, Vahe Amassian, John Rothwell of the Institute of Neurology, Queen Square, London, Mark S. George, MD of the Medical University of South Carolina, David H. Avery, MD of the University of Washington at Seattle, Charles M. Epstein of Emory University, Drs. Mark Hallett, Leonardo G. Cohen, and Eric Wassermann of the National Institutes of Health, and Alvaro Pascual-Leone of Harvard Medical School. Currently, thousands of TMS stimulators are in use. More than 3000 scientific publications have been published describing scientific, diagnostic, and therapeutic trials.

[edit] How TMS affects 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. The pulse(s) causes a population of neurons in the neocortex to depolarise and discharge an action potential. If used in the primary motor cortex, it produces a motor-evoked potential (MEP) which can be recorded on electromyography (EMG). If used on the occipital cortex, 'phosphenes' (flashes of light) might be detected 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 Positron Emission Tomography or fMRI. These effects do not outlast the period of stimulation. A review of TMS can be found in the Handbook of Transcranial Magnetic Stimulation.^[2]

• Repetitive TMS (rTMS) produces effects which last longer than the period of stimulation. rTMS can increase or decrease the excitability of corticospinal or corticocortical pathways depending on the intensity of stimulation, coil orientation and frequency of stimulation. 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). A recent review of rTMS can be found in Fitzgerald et al, 2006^[3].

As such, it is important to distinguish TMS from repetitive TMS (rTMS) as they are used in different ways for different purposes.

[edit] TMS and rTMS techniques in research

One reason TMS is important in cognitive psychology/neuroscience is that it can demonstrate causality. A noninvasive mapping technique such as fMRI allows researchers to see what regions of the brain are activated when a subject performs a certain task, but this is not proof that those regions are actually used for the task; it merely shows that a region is associated with a task. If activity in the associated region is suppressed (i.e. 'knocked out') with TMS stimulation and a subject then performs worse on a task, this is much stronger evidence that the region is used in performing the task.

For example: subjects asked to memorize and repeat a stream of numbers would likely show activation in the prefrontal cortex (PFC) via fMRI, indicating the role of this brain region in short-term memory. If the researcher then interfered with the PFC via TMS, the subjects' ability to remember numbers would decline, and the researcher would have evidence that the PFC is important for short-term memory, because reducing subjects' PFC capability led to reduced short-term memory.

This ‘knock-out’ technique (also known as virtual lesioning) can be done in two ways:

• Online TMS: where subjects perform the task and at a specific timepoint (usually in the order of 1-200ms) of the task, a TMS pulse is given to a particular part of the brain. This should affect the performance of the task specifically, and thus demonstrate that this task involves this part of the brain at this particular time point. The advantage of this technique is that any positive result can provide a lot of information about how and when the brain processes a task, and there is no time for a placebo effect or other brain areas to compensate. The disadvantages of this technique is that in addition to the location of stimulation, one also has to know roughly when the part of the brain is responsible for the task so lack of effect is not conclusive.

• Offline repetitive TMS: where performance at a task is measured initially and then repetitive TMS is given over a few minutes, and the performance is measured again. This technique has the advantage of not requiring knowledge of the timescale of how the brain processes. However offline repetitive TMS is very susceptible to the placebo effect due to the contribution of dopamine to the placebo effect^[4]. Additionally, the effects of repetitive TMS are variable between subjects and also for the same subject. A variant of this technique is the ‘enhancement’ technique, where repetitive TMS is delivered to enhance performance. This is even harder to achieve than the ‘knock-out’ technique.

[edit] Risks of TMS and rTMS

As it induces an electrical current in the human brain, TMS and rTMS can produce a seizure.^[5][6] The risk is very low with TMS except in patients with epilepsy and patients on medications. The risk is significantly higher, but still very low, in rTMS especially when given at rates >5Hz at high intensity.
The only other effects of TMS which are reported in most subjects are:

• Discomfort or pain from the stimulation of the scalp and associated nerves and muscles on the overlying skin^[6]
• Hearing the loud click made by the TMS pulse

The long-term effects of TMS remain unknown,^[5] although no effects on cognitive capacities (such as memory) have been reported yet.^[6]

[edit] Clinical uses of TMS and rTMS

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

[edit] TMS for diagnostic purposes

TMS is used currently 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 (i.e. MEP amplitude, MEP latency, central motor conduction time). This is most useful in stroke, spinal cord injury, multiple sclerosis and motor neuron disease. There are numerous other measures which have been shown to be abnormal in various diseases but few are validated or reproduced and more importantly, no one knows the significance of these measures. The most famous is short-interval intracortical inhibition (SICI) which measures the internal circuitry (intracortical circuits) of the motor cortex described by Kujirai et al. in 1993.^[7]

Plasticity of the human brain can also be measured now with repetitive TMS (and variants of the technique, e.g. theta-burst stimulation, paired associative stimulation) and it has been suggested that this abnormality of plasticity is the primary abnormality in a number of conditions.

[edit] TMS for therapeutic purposes

A large number of studies with TMS and rTMS have been conducted for a variety of neurological and psychiatric conditions but few have been confirmed and most show very modest effects, if any. Some conditions which have been reported to be responsive to TMS-based therapy are:

• Stroke
• Nonfluent aphasia ^[8]
• Tinnitus
• Parkinson’s Disease
• Dystonia
• Amyotrophic lateral sclerosis
• Epilepsy
• Migraine^[9]
• Dysphasia
• Hemispatial neglect
• Major depression (rTMS therapy for drug-resistant depression has been approved by Health Canada for clinical delivery since 2002).
• Phantom limb
• Chronic pain
• Obsessive-compulsive disorder
• Auditory Hallucinations associated with Schizoaffective Disorders
• Fibromyalgia

It is important to stress that in most of these studies, no adequate control of placebo effect was possible and thus it is tempting to wonder if this effect is placebo.^{[citation needed]} This is especially true since the conditions it work best for are conditions one would think a placebo would do best at treating. This will always be the case, because no double blind experiment is possible. Logically if it had any effect on the patient's neurons, the patient could detect it.

It is also important to realise that white coat syndrome can be a temporary treatment as well as a temporary protagonist. One could never be sure whether white coat syndrome was at work or not, because the double blind could never be assured.

[edit] TMS equipment

The major manufacturers for general purpose TMS and repetitive TMS equipment are:

• The Magstim Company, UK
• MagVenture A/S, Denmark
• Nexstim, Finland
• Schwarzer, Germany
• Neuronetics, Inc., USA

As regulated medical devices, TMS devices are not sold to the general public. They are also expensive (US$25,000-100,000 for basic equipment; US$500,000 for state-of-the-art targeting and recording instruments). In Europe, TMS devices that have been manufactured according to the Medical Device Directive have been granted the CE mark and can thus be freely marketed within the EU.

[edit] FDA approval

As of October 8, 2008, a TMS device, NeuroStar, manufactured by Neuronetics Inc. has been approved for use by the US Food and Drug Administration (FDA) for use in adult patients with major depression who have previously tried medication and not improved satisfactorily.^[10]

Several TMS/rTMS devices are approved by the FDA for stimulation of peripheral nerve and, therefore, can be used "off label" by individual physicians to treat brain disorders, essentially in any way they believe appropriate, analogous to the off label use of medications. However, most legitimate use of TMS in the USA and elsewhere is currently being done under research protocols approved by hospital ethics boards and, in the US, often under Investigational Device Exemption from the U.S. Food and Drug Administration (FDA). The requirement for FDA approval for research use of TMS is determined by the degree of risk as assessed by the investigators, the FDA, and the local ethics authority.

[edit] Technical information on TMS

TMS is simply the application of the principle of induction to get electrical current across the insulating tissues of the scalp and skull without discomfort. A coil of wire, encased in plastic, is held to the head. When the coil is energized by the rapid discharge of a large capacitor, a rapidly changing current flows in its windings. This produces a magnetic field oriented orthogonally 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 flows tangentially with respect to skull. The current induced in the structure of the brain activates nearby nerve cells in much the same way as currents applied directly to the cortical surface. The path of this current is complex to model because the brain is a non-uniform conductor with an irregular shape. With stereotactic MRI-based control, the precision of targeting TMS can be approximated to a few millimeters (Hannula et al., Human Brain Mapping 2005).

Typical data: ^[11]

• magnetic field: often about 2 teslas on the coil surface and 0.5 T in the cortex
• current rise time: zero to peak, often around 70-100 microseconds
• wave form: monophasic or biphasic
• repetition rate for rTMS: below 1 Hz (slow TMS), above 1 Hz (rapid-rate TMS)

[edit] TMS 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 (ie, the so-called ‘air-core’coil design), or possess a solid, ferromagnetically active material (ie, 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 (eg, 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. ^[12][13]

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

• Deep TMS (or H-coil): currently being used in a clinical trial for the treatment of patients suffering from clinical depression.^[14]

[edit] References

• Highfield, Roger (16 May, 2008). "How a magnet turned off my speech". Daily Telegraph. "Words failed me. I stuttered as Prof Vincent Walsh turned off the speech centre of my brain for a few thousandths of a second to demonstrate the power of transcranial magnetic stimulation, a popular way to interfere with the most complex known object in the universe." 

[edit] See also

• Cranial Electrotherapy Stimulation (CES)
• Transcranial direct current stimulation (tDCS)
• Electroconvulsive therapy (ECT)

[edit] External links

• Transcranial magnetic stimulation in psychiatry
• Magnets may make the brain grow stronger
• The Avery-George-Holzheimer Database of rTMS Depression: Excellent overview of all studies up to 2004!
• "Transcranial Magnetic Stimulation" from Scholarpedia
• Front page Wall Street Journal article describing TMS for "intractable cases of depression