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Transcranial magnetic stimulation
 Transcranial magnetic stimulation (TMS) is a noninvasive method to excite neurons in the brain. The excitation is caused by weak electric currents induced in the tissue by rapidly changing magnetic fields (electromagnetic induction). This way, brain activity can be triggered or modulated without the need for surgery or external electrodes. This is used to study the circuitry and connectivity of the brain. Repetitive transcranial magnetic stimulation is known as rTMS and can produce longer lasting changes. Numerous small-scale pilot studies have studies have shown it could be a treatment tool for various neurological conditions (e.g. migraine, stroke, dystonia), but as yet no large scale trial has been done, the therapeutic potential of rTMS should not be considered proven.

Background
The principle of inductive brain stimulation with eddy currents has been noted since the 19th century. The first successful TMS study was performed by Anthony Barker et al.[2] 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 is limited by severe discomfort. By stimulating different points of the cortex and recording responses, e.g., from muscles, one may obtain maps of functional brain areas. By measuring EEG, information may be obtained about the healthiness of the cortex (its reaction to TMS) and about area-to-area connections.

It is also important to distinguish TMS from repetitive TMS (rTMS) as they are used in different ways for different purposes.

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.[4]

•	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 mechanisms of these effects are 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.[5]

TMS and rTMS in research
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, Prof. Mark Hallett, Leonardo G. Cohen, and Eric M. 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.

TMS and rTMS research techniques
One reason TMS is important in 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 (‘knocked out’ or ‘lesioned’) 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, via fMRI, activation in the prefrontal cortex (PFC), which seems to be important 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 can be done in two ways:''


 * 1) 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 one has to know roughly when the part of the brain is responsible for the task so lack of effect is not conclusive.


 * 1) 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 repetitive TMS is very susceptible to the placebo effect. 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.

Risks of TMS and rTMS
As it induces an electrical current in the human brain, TMS and rTMS can produce a seizure. The risk is very low with TMS except in patients with epilepsy and patients on medications. The risk is significantly higher 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/ pain from the stimulation of the scalp and associated nerves on the overlying skin


 * hearing from the loud click made by the TMS pulse

TMS for diagnosis
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 it. The most famous is short-interval intracortical inhibition (SICI) which measures the internal circuitry (intracortical circuits) of the motor cortex (Kujirai et al., 1993).

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 is the primary abnormality in a number of conditions.

TMS for therapy
It is important to stress that there is no strong evidence for the use of TMS for therapy of any condition. A large number of studies with TMS and repetitive TMS has 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 (but not proven) to be responsive to TMS-based therapy are:


 * Stroke


 * Tinnitus


 * Parkinsons Disease


 * Dystonia


 * Epilepsy


 * Migraine


 * Dysphasia


 * Neglect


 * Chronic pain


 * Depression

It is important to stress that in a vast majority of these studies, no adequate control of placebo effect was possible and thus it is tempting to wonder if this effect is placebo.

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 specifications:

Magnetic field: often about 2 tesla on the coil surface and 0.5 T in the cortex

Current rise time: zero to peak, often around 70-100 microseconds

Waveform: monophasic or biphasic

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


 * The Magstim Company, UK


 * Medtronics, USA


 * Cadwell, USA


 * Dantec, Denmark


 * Schwarzer, Germany

Several TMS/rTMS devices are approved by the US Food and Drug Administration (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 US 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 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. An application for clearance of TMS Therapy as a treatment for depression was submitted to the FDA in 2006. The FDA convened its Neurological Devices Panel on January 26, 2007 to review the TMS Therapy application. The results of this panel meeting were mixed with no concerns regarding the safety of this treatment, however, there was clear questioning of the efficacy of this treatment [7]. A final decision from the FDA in regard to approving TMS as a treatment for depression is expected in the first half of 2007. As regulated medical devices, TMS devices are not sold to the general public. They are also expensive (US$25,000-100,000; together with state-of-the-art targeting and recording instruments, up to about US$500,000). 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.