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History

In the late 18th century, Luigi Galvani began laying the foundations for modern electrophysiology and bioelectric theory. While working with a frog sciatic nerve- gastronomies muscle preparation, Galvani showed that the muscle could be made to contract if a zinc electrode attached to the muscle and a copper electrode attached to the nerve were brought in contact with each other. Galvani incorrectly concluded that the contractions were the result of "animal electricity" released from storage in the muscle, only to return via the closed zinc and copper path through the nerve. In 1793, one year after Galvani's initial publication on "animal electricity", the Italian physicist Alessandro Volta proposed that the electrical stimulus responsible for the contraction was due to dissimilar electrical properties at the metal-tissue saline interfaces. It was not until 1800 that Volta conclusively proved the stimulus was of electrical origin, showing that the voltage difference due to the unbalanced half-cell potentials of the zinc-saline and copper-saline interfaces excited the neuromuscular preparation. Subsequently, Volta invented the first wet-cell battery called the "Voltaic cell"- constructed by placing metal and saline cells in series. The early work of Galvani and Volta provided physiologists with an early understanding of the mechanisms of neural and muscular excitation. While the mechanistic details would not become clear until nearly 150 years later, it was understood that neural and muscular signals could be generated and carried through electrical means.

During the early part of the 1800's Italy's Felice Fontana took the work of Volta and Galvani one far-reaching step further. Using a series of voltaic cells, Fontana carried out the first known human brain stimulation experiments on cadavers, invoking facial spasms in the recently deceased through the application of the voltaic cell to specific brain regions. Public concern over his experiments led to an eventual law forbidding the cadaver work; Fontana responded by continuing his work with living volunteers. Throughout the 19th century continued advances were made in both electrophysiology and electromagnetic theory laying the foundation for the currently pervasive form of brain stimulation- magnetic stimulation. Magnetic stimulation in its most primitive form was first investigated at the end of the nineteenth century by physicists studying fundamental aspects of electromagnetics and in particular the implications of Faraday's Law. In 1896, the famous physicist and physician d'Arsonval reported on his paper entitled "Apparatus for Measuring Alternating Currents of All Frequencies," that "an intensity of 110 volts, 30 amperes with a frequency of 42 cycles per second, gives rise to, when one places the head into the coil, phosphenes and vertigo". Independently in 1910 Sylvanias Thompson (see Figure 1) reported similar findings of perceived magnetophosphenes, the visual excitations of the retina induced by the time varying magnetic fields (now it is understood that magneto-phosphenes can be initiated from the stimulation of the retina or occipital cortex- but it is clear that early experiments produced phosphenes of retinal origin). While these physicists have primarily been remembered for their contributions to the field of electromagnetics, they were of the first scientists to study magnetic brain stimulation by non-invasively inducing magnetophosphenes in subjects.

Magnetophosphene research continued on sporadically throughout the first half of the twentieth century, but over half a century passed before time-varying magnetic fields were used to stimulate isolated nerves. In 1959 Kolin et al. clearly demonstrated that time varying magnetic fields could be used to initiate muscle contractions in frog sciatic nerve, gastronomies-muscle preparations. They applied both 60 (check this fact) and 1000 Hz fields of varying intensity to the sciatic nerve, wrapped around the insulated electromagnetic source, and easily induced an intense contraction in the muscle. They did not however directly record the neural or muscle action potentials, but rather recorded the muscle displacement via a force transduction mechanism. In 1965 Brickford and Flemming non-invasively stimulated peripheral nerves within intact frogs, rabbits, and humans through a pulsed magnetic field (2-3 Tesla pulse over 300 ms). They concluded that "stimulation results from eddy currents induced in the vicinity of motor nerves" but were unable to record the nerve or muscle action potentials due to the limitations of their recording equipment in removing the noise caused by the stimulating device. Thus, they did not further pursue their work.

Others including Irwin, Maass, and Oberg continued the work. But more often than not, magnetic stimulation was overlooked in lieu of the more tractable direct electrical stimulation. Many of the early magnetic stimulation devices were technically difficult to operate and oftentimes prone to extreme overheating in addition to the aforementioned interference problems associated with the stimulating fields. In 1976, Barker generated an electromagnetic device capable of generating peak fields of 2 Tesla with an approximate rise time of 100 ms for the study of velocity selective stimulation of peripheral nerves. This work served as a precursor to developing a stable and reliable magnetic stimulator. In 1982 Polson, Barker, and Freeston described the design of a stimulator proven effective in peripheral nerve stimulation that did not suffer from the earlier technical difficulties associated with magnetic stimulation. Subsequently, in 1985 Anthony Barker and his group at the University of Sheffield and the associated Royal Hampshire Hospital introduced Transcranial Magnetic Stimulation (TMS), a non-invasive technique that uses the principles of electromagnetic induction to focus currents in the brain and modulate the function of the cortex. In 1985, at the 11th International Congress of Electroencephalography and Clinical Neurophysiology in London and at the Physiological Society in Oxford public demonstrations (see Figure 2) produced great clinical and scientific interest. To facilitate the acceptance and proliferation of the technique the Sheffield group encouraged the commercial development of magnetic stimulators by interested parties.

In 1985 the first clinical studies of TMS began and in 1987 Barker's group released the first safety guidelines for the procedure. TMS proved to be superior to electrical stimulation as a way to non-invasively stimulate the brain because electrical analogs are painful and difficult to implement. In 1986, clinical interest was even further augmented when the Cadwell Corporation made commercial stimulators available that could provide stimulation rates up to 60 Hz pulsed 1-2 Tesla peak fields. Today TMS is classified as either single pulse TMS (0.3-0.5 Hz) or repetitive TMS (rTMS).