Mark S. George and Joseph J. Taylor
The mechanisms underlying human behavior have intrigued physicians, scientists, and philosophers for centuries. As early as 250 B.C.E., theories about pseuma psychikon, or “animal spirits,” emerged as explanations for nervous system function. These perspectives became dogma through the teachings of Galen of Pergamum (129–216), a Greek physician who viewed nerves as hollow conduits through which animal spirits flowed. These spirits began to be associated with the brain through the experiments of William Harvey (1578–1657) and the philosophical musings of René Descartes (1596–1650; Brain, 1959; Cobb, 2002). In some ways, Descartes’ position was a curious amalgam of scientific hypotheses from the modern-day 1600s and ethereal hypotheses from antiquity. When Jan Swammerdam (1637–1680) demonstrated that mechanical stimulation of a nerve could contract a muscle, the scientific community began to search for new methods of exploring nervous system function.
Following the rediscovery of electricity and magnetism in the 1700s, electromagnetic stimulation emerged during investigations of how the brain moves the body. With the advent of the first capacitor, known as a Leyden jar, experiments gradually began to support Luigi Galvani’s (1737–1798) concept of animal electricity over Alessandro Volta’s (1745–1827) concept of bimetallic electricity or Franz Mesmer’s (1734–1815) concept of animal magnetism. Coining the term “galvanism,” Galvani’s precocious nephew Giovanni Aldini (1762–1834) in Italy began exploring the effects of electricity on decapitated livestock and cadavers. Shortly after his reanimation experiments, Aldini began applying galvanism to ameliorate “melancholy madness” in hospital patients.
Aside from potentially serving as an inspiration for Mary Shelly’s 1818 novel Frankenstein, Aldini’s macabre methodology was also critical for establishing interest in brain stimulation leading into the 19th century. Capitalizing on a serendipitous observation during the War of 1864, Gustav Fritz (1838–1927) and his colleague Eduard Hitzig (1838–1907) used direct current in galvanic form to discover the motor cortex. This important discovery inspired David Ferrier (1843–1928), a neophyte physician who had recently completed medical school at the University of Edinburgh, to accept a position at the West Riding Lunatic Asylum in York, England. It was there that Ferrier found a supportive environment in which to carry out his own stimulation experiments on birds and mammals.
Improving upon Fritz and Hitzig’s technique, Ferrier began stimulating animal brains using alternating current rather than direct current because it provided superior stimulus control and enabled him to provoke more discrete effects. Ferrier used this technology to stimulate movement-related brain areas in animals that had undergone craniotomy using a new form of ether-based anesthesia. This direct electrical brain stimulation enabled Ferrier to titrate and localize motor function, even after the subjects had recovered from anesthesia. Ferrier also performed ablation studies. After completing these revolutionary experiments, Ferrier published his results in the West Riding Lunatic Asylum Medical Reports. His work was well received in scientific circles. Soon thereafter, Ferrier moved from York to London and was elected as a member of the Royal Society. In London, Ferrier began studying macaque monkeys because their brains were similar to those of human beings. He continued to explore the motor cortex but also attempted to find the cerebral centers that mediate sight and hearing.
The highlight of David Ferrier’s career was the publication of Functions of the Brain, an 1876 manuscript in which he summarized his own work along with the available neurophysiological knowledge. The book was dedicated to Hughlings Jackson (1835–1911), a mentor with whom Ferrier worked in London. In addition to this book, Ferrier is also known for serving as cofounder of the famous journal Brain (1878), which actually evolved from the West Riding Lunatic Asylum Reports. In that same year, Ferrier published a second book, The Localisation of Cerebral Disease. This time, Ferrier dedicated his work to Jean-Martin Charcot (1825–1893), a French neurologist and fellow localizationist. Although most of the localization experimenters used brain stimulation as an investigational tool, their work inspired future generations to also explore brain stimulation as potential therapy.
By 1820, scientists knew that passing electric current through a wire induced a magnetic field. This principle is commonly demonstrated by a grade-school experiment in which students create an electromagnet using a nail, a wire, and a battery. In 1832, Michael Faraday (1791–1867) showed that the opposite is also true; a pulsing magnetic field (e.g., a magnet passing through a metal coil) induces electric current (Higgins and George, 2009). The first forms of noninvasive brain stimulation were based on these ideas. James Clerk Maxwell then built on this work, bringing together electricity and magnetism, and in 1861 published his equations, which form the foundation of classic electrodynamics and electric circuits. In lay language, Maxwell’s equation explained that whenever an electrical current flows there is a corresponding magnetic field generated.
The idea of using transcranial magnetic stimulation (TMS), or something akin to it, to alter neural function emerged during the late 19th century. In 1896, Jacques-Arsène d’Arsonval (1851–1940) reportedly used a magnetic coil device to induce phosphenes (flashes of light arising from visual cortex stimulation without the actual presence of an external light source) (Theodore, 2002). In 1902, Adrian Pollacsek (1850–1921) and Berthold Beer (1859–1922) filed a patent for an electromagnetic device designed to treat depression and neuroses (Beer, 1902). Ironically, these two psychiatrists were working just a few miles away from Sigmund Freud in Vienna. In 1910, there was a flurry of work using TMS to induce phosphenes (Thompson, 1910). Although electromagnets were used to contract peripheral frog muscles in 1959 (Kolin, Brill, and Broberg, 1959), they did not resemble modern TMS coils until 1985 when Anthony Barker and colleagues developed one to stimulate human motor cortex (M1; Barker, Jalinous, and Freeston, 1985; Higgins and George, 2009). In 1995, Mark George and colleagues demonstrated the clinical use for TMS in depression. Their initial open-label study, which was followed quickly by a double-blind study (1996), found that daily repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) significantly improved mood in depressed individuals (George et al., 1997). One patient even experienced complete remission for the first time in three years (George et al., 1995). This seminal study sparked years of research that led the U.S. Food and Drug Administration to approve left PFC rTMS for treatment-resistant depression (Hadley et al., 2011; O’Reardon et al., 2007).
Modern TMS coils work in a fashion similar to that of the coil developed by Barker and colleagues in the 1980s. TMS is a focal, noninvasive form of brain stimulation that can depolarize or hyperpolarize superficial cortical neurons in the human brain (George, 2003). Administration of TMS typically involves positioning an electromagnetic coil on the scalp. This coil uses electrical current to create powerful (approximately 1.5 Tesla) yet brief (approximately microseconds) magnetic fields that enter the brain unimpeded by electrical resistors such as skin, muscle, and skull. In accordance with theories of electromagnetism discussed previously and developed by James Clerk Maxwell (1831–1879), Michael Faraday, and others in the 19th century (Horwitz, 1994; Morabito, 1999), pulsing magnetic fields induce electric current in neuronal membranes. Thus, electrical energy in the TMS coil is transformed into magnetic energy that traverses the skull. This magnetic energy is converted back into electrical energy in the brain (Bohning, 2000).
Although its immediate effects are superficial and focal, TMS may also modulate cortical and subcortical structures that are synaptically connected to the region being stimulated. Successive trains of pulses, known as repetitive TMS (rTMS), may enhance the local and distributed effects of single-pulse TMS. These staccato magnetic fields have the capacity to induce neurophysiological changes that persist after the stimulation paradigm ends (George and Aston-Jones, 2010; George et al., 2010). It is for this reason that rTMS has been explored as a therapeutic intervention for neuropsychiatric disorders such as treatment-resistant depression (Johnson et al., 2012; Janicak et al., 2010; Mantovani et al., 2012; Carpenter et al., 2012) and pain (Borckardt et al., 2006, 2008; Mylius, Borckardt, and Lefaucheur, 2012).
One of the basic tenets of rTMS therapy is that its behavioral effects persist after the stimulation paradigm ends. This principle has been demonstrated throughout the TMS literature (George and Aston-Jones, 2010; George et al., 2010). Changes in motor-evoked potentials, for example, suggest that rTMS alters cortical excitability in a frequency-dependent manner (Hallett, 2000). Whereas high-frequency stimulation (e.g., 10 Hz) increases cortical excitability, low-frequency stimulation (e.g., 5 Hz) decreases cortical excitability. The mechanisms by which these neuroadaptations occur remain unclear, but some have speculated that rTMS induces a Hebbian plasticity that resembles long-term potentiation (LTP) or long-term depression (LTD). In laboratory animals, TMS has been shown to induce LTP-and LTD-like phenomena in vivo and in vitro (Ahmed and Wieraszko, 2006, 2008; Teo, Swayne, and Rothwell, 2007; Huang, Chen, Rothwell, and Wen, 2007; Wang, Wang, and Scheich, 1996; Tokay, Holl, Kirschstein, Zschorlich, and Kohling, 2009). These physiological changes have been shown to correspond to changes in behavioral measures (Kim et al., 2006) and second messenger systems implicated in neuroplasticity (Aydin-Abidin, Trippe, Funke, Eysel, and Benali, 2008, Feng et al., 2012).
Human studies of rTMS-induced plasticity typically focus on the manifestations of such plasticity rather than the mechanisms that underlie it. One way to analyze rTMS-induced plasticity is to stimulate offline and then use functional magnetic resonance imaging (fMRI) blood oxygen level–dependent signal changes evoked by a behavioral task as a “functional readout” of stimulation-induced plasticity. Another way to manipulate and understand rTMS-induced plasticity is to use paradigms such as theta burst stimulation that have been well characterized in the animal neurophysiology literature. Studies have used theta burst rTMS both as a therapeutic tool to affect behavioral outcomes (Chistyakov, Rubicsek, Kaplan, Zaaroor, and Klein, 2010; Galea, Albert, Ditye, and Miall, 2010; Ott, Ullsperger, Jocham, Neumann, and Klein, 2011; Verbruggen, Aron, Stevens, and Chambers, 2010) and as an investigational tool to examine neurophysiology (Tupak et al., 2011; Ko et al., 2008; Cho et al., 2012; Grossheinrich et al., 2009).
Novel ways to study rTMS-induced neuroplasticity can result when existing tools and methods are combined in ways that improve upon limitations. Using interleaved TMS/fMRI to measure excitability changes induced by rTMS in nonmotor brain regions is one example of this approach. Another example is TMS combined with electroencephalography (EEG). This complicated technique has provided insight into clinical disorders (Barr, Farzan, Davis, Fitzgerald, and Daskalakis, 2012; Weaver et al., 2012; Benninger et al., 2012) as well as neurophysiological indices such as short latency afferent inhibition and interhemispheric signal propagation (Daskalakis, Farzan, Radhu, and Fitzgerald, 2012). As analysis of TMS-EEG data becomes more sophisticated (Hernandez-Pavon et al., 2012; Bijsterbosch, Barker, Lee, and Woodruff, 2012), so too might the understanding of how rTMS affects local and inter-hemispheric neurophysiology.
TMS is a focal, noninvasive form of brain stimulation based on principles of electromagnetic induction that have been well established for nearly 200 years. Throughout history, brain stimulation techniques such as TMS have proved to be powerful tools for investigating neurophysiology as well as for mapping and modulating neural circuitry.
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