The Science of Transcranial Magnetic Stimulation

William M. Sauvé, MD; and Lawrence J. Crowther, MEng

ABSTRACT Transcranial magnetic stimulation (TMS) is a noninvasive method for stimulating neural tissue based on the principles of electromagnetic induction. The technique is becoming an established treatment for drug-resistant major depressive disorder and is a promising tool for a variety of psychiatric and neurologi- cal disorders. Stimulation is achieved by pulsed magnetic !elds inducing electric !elds with the necessary characteristics to depolarize neurons, generating action potentials. In this article, the underlying principles and mechanisms of TMS are explored and an overview of the devel- opment of stimulator devices is provided. [Psychiatr Ann. 2014; 44(6):279–283.]

William M. Sauvé, MD, is Medical Direc- tor, TMS NeuroHealth Centers, Richmond. © Shutterstock Lawrence J. Crowther, MEng, is Graduate Research Assistant, Department of Electri- ince the days of Pliny, humans have phenomenon has only recently been used cal and Computer Engineering, Iowa State been curious about the effects of as a therapeutic modality in psychiatry. University. Selectrical stimulation on the body, Known as repetitive transcranial magnetic Address correspondence to: William M. and since Michael Faraday famously de- stimulation (rTMS), it was approved for Sauvé, MD, TMS NeuroHealth Centers, 5231 veloped the concept of electromagnetic the treatment of major depressive disorder Hickory Park Drive, Suite C, Glen Allen, VA induction, it has been understood that by the U.S. Food and Drug Administration 23059; email: [email protected]. changing magnetic fields can cause current in 2008. What follows is a very basic over- Disclosure: Dr. Sauvé is employed by TMS to flow in conductive material,1 including view of the underlying physics of TMS, NeuroHealth Centers. Mr. Crowther has no the brain. Although the ability to stimulate how it impacts the neurons in the brain, relevant financial relationships to disclose. the brain using magnetic pulses was estab- some of the methods of application, and doi:10.3928/00485713-20140609-05 lished by Jacques d’Arsonval in 1896,2 this the various stimulation devices in use.

039#()!42)#!..!,3s6OL .O 279 CME Copyright 2014 SLACK Inc. FARADAY’S LAW OF a neuron, two major factors include chro- be an important part of learning.6 LTP was ELECTROMAGNETIC INDUCTION naxie and rheobase. Chronaxie is defined first described by Terje Lømo in 1966, Both Michael Faraday and Joseph as the minimum time for an electric cur- showing that while a single electric stimu- Henry independently discovered the con- rent to double the strength of the rheobase lus delivered to presynaptic fibers resulted cept of electromagnetic induction in 1831, of a neuron; rheobase is defined as the in excitatory postsynaptic potentials in the but Faraday was the first to publish his lowest intensity of current that can cause postsynaptic cells, high-frequency trains findings. Simply put, a magnetic field that an action potential in said neuron.4 of stimuli delivered to the same resulted is in motion relative to a conductor brings Thus, when a magnetic field pulses in an enhanced response over an extended about a current in said conductor. Hence, adjacent to the volume conductor, which period of time. He called this phenom- a changing magnetic field induces a flow in this case is the brain, an electrical field enon “long-lasting potentiation,”7 which of electric current in nearby conductors is generated at sufficient strength and du- was later changed to “long-term potentia- that, for the purposes of this article, in- ration to cause the neuron to depolarize, tion” by Douglas and Goddard in 1975.8 clude human tissue.3 The most commonly resulting in an action potential. When the LTD is the opposing process to LTP, used form of expression for this concept motor cortex is stimulated in this way, with the efficacy of neuronal synapses be- is the Maxwell-Faraday equation, also re- the result is a motor evoked potential ing decreased after certain stimuli. LTD is ferred to as Faraday’s Law. (MEP), leading to motor activity. Simi- thought to result mainly from a decrease Electromagnetic induction is the key lar single or paired pulse TMS delivered in postsynaptic receptor density, with L- principle in transcranial magnetic stimu- over the occipital cortex has also resulted glutamate interacting with multiple re- lation (TMS), taking advantage of the fact in flashes of light being perceived by the ceptors to selectively weaken receptor that every electric current has a magnetic subject. Pulses delivered over other parts strength. Some examples of the utility of field surrounding it, with alternating cur- of the brain may not be experienced on LTD can be the possible clearing of old rents bringing about fluctuating magnetic the conscious level but have resulted in memory traces in the hippocampus9 and fields. Fluctuating magnetic fields in turn measurable changes, such as on the sub- the concept of neuroplasticity in general, cause electric current to flow in conduc- ject’s performance in a cognitive task. with LTP and LTD occurring in concert to tors placed within them; the conductors Practical application of TMS, however, selectively strengthen and weaken synap- in the case of TMS being neurons in the is largely focused on rTMS, where such tic connections in the brain. It is the pos- brain, thus allowing for electrical stimula- pulses are being delivered in trains at cer- sible modulation of these phenomena by tion of neurons within the brain in a non- tain frequencies that have been shown to rTMS that may explain some of its lasting invasive fashion. generate more lasting effects. Generally, effects and clinical utility. by mechanisms that are not well under- DIRECT NEURONAL EFFECTS OF TMS stood, low-frequency stimulation (!1 Hz) DEFINING PULSE SEQUENCES It has been demonstrated that a mag- is thought to bring about reduced corti- Determining pulse sequences requires netic field pulsed adjacent to a volume cal excitability, whereas high-frequency that decisions be made about frequency, conductor (such as the brain) induces an stimulation (>5 Hz) increases cortical intensity, and duration of stimulation. electrical field in that conductor. Although excitability and, in each case, the effect Frequency of stimulation will be chosen the brain is truly a heterogeneous con- is maintained for some time after a num- based on the desired effect, either an in- ductor, with the white and gray matter as ber of pulse trains have been completed. crease or decrease in cortical excitability in well as cerebrospinal fluid all having dif- Again, the mechanism is not well un- the area being stimulated, with an increase ferent conductivities (0.48, 0.7 and 1.79 derstood but may be partly explained by typically brought about by high-frequency siemens/m, respectively),3 the resultant the phenomena of long-term potentiation pulse trains, and a decrease brought about differences in the induced electric field are (LTP) and long-term depression (LTD).5 by low-frequency pulse trains. For exam- small enough that the brain can be thought ple, the approved treatment for depression of as a homogeneous volume conductor. LONG-TERM POTENTIATION/ consists of 4-second pulse trains at 10 Hz Furthermore, the induced current is small DEPRESSION delivered to the left-side dorsolateral pre- enough so as not to have any effect on the LTP refers to a process by which syn- frontal cortex and is thought to generate magnetic field, thus eddy currents are not aptic communication between neurons is an increase in cortical excitability in this significant in this case, making the induc- made more efficient when said neurons area. Conversely, some small studies in the tion of an electric field within the brain via fire in sequence. Often remembered in treatment of Tourette syndrome have used TMS a one-way proposition. school by the saying “neurons that fire to- a frequency of 1 Hz stimulation over the When discussing the effect of TMS on gether, wire together,” LTP is thought to supplementary motor area (SMA), with

280 #OPYRIGHT¹3,!#+)NCORPORATED CME Copyright 2014 SLACK Inc. the expectation that cortical excitability seconds for a total of 191.84 seconds, or a meaning circular coils do not produce a will be decreased as a result.10 total of 600 pulses, with continuous TBS single area of maximum field. Circular Intensity of stimulation is affected by being defined as three pulses at 50 Hz coils do, however, offer the ability to stim- many variables but is largely dictated by repeated every 200 ms for 20 or 40 sec- ulate both hemispheres at the same time the baseline excitability of the cortex, onds for a total of 300 or 600 pulses. TBS to some degree by placing the coil at the which can be measured by the minimum protocols remain in the investigational cranial vertex, although the direction of stimulation required to bring about an stage, with the main potential advantage induced current has an influence over the MEP. In clinical practice, this is often being that similar effects to rTMS may be extent to which neuronal activation can be determined by the observation of muscle achieved with considerably shorter pro- achieved in the motor cortex, with a pref- movement in the subject being stimulated tocols leading to similar or even greater erence for currents flowing from posterior and is called the resting motor threshold duration of either excitatory or inhibitory to anterior. Flat circular coils are still used (RMT). Stimulus intensity in various pro- after effects. and commercially produced15,16 but have tocols will then be expressed as a percent- been succeeded by more complex designs age of RMT (eg, the approved treatment TMS STIMULATOR DESIGN for therapeutic implementation. In 1998, for depression is typically performed at an TMS stimulators generate the pulsed Ueno et al.17 proposed the figure-8 coil, intensity of 120% of RMT). electrical current needed by TMS coils also known as a butterfly coil, as a method The duration of a pulse train may have to produce the transient magnetic field of achieving localized stimulation by plac- an effect on the duration of the after ef- necessary for stimulation of neural tissue. ing two coils side by side with currents fects. In the motor cortex, a 15-minute Energy is stored within a large capacitor flowing in the same direction where the train of rTMS at approximately 1 Hz re- that is discharged by a silicon-controlled two coils meet. The resulting induced elec- duces cortical excitability for at least the rectifier switch designed to minimize tric fields add together, allowing focused subsequent 15 minutes, whereas single- losses and be capable of carrying currents stimulation. Although the localization of pulse stimulations have been shown to of thousands of amps. The nature of the stimulation can be greatly increased with only change cortical excitability for ap- discharged current depends on the reso- a figure-8 coil, the decay of electric field proximately 200 ms.11 nant frequency of the stimulator circuitry. within a homogeneous volume conduc- It is important to note, however, that In the case of TMS, the rate of change tor has been shown to occur more rapidly many studies on cortical excitability follow- of current and subsequent magnetic field for a figure-8 coil compared to a circular ing pulse sequences varying in frequency, with respect to time is the primary con- coil,18,19 reducing its ability to stimulate intensity, and duration are either inconsis- sideration. Two main types of magnetic deeper brain regions. tent or even contradictory. For practical pur- stimulators exist and are distinguished by poses it is useful to work with the paradigm the characteristics of the pulse they pro- MODIFICATIONS TO TMS COILS AND that high-frequency tends to increase corti- duce: monophasic and biphasic. Mono- USE OF IRON CORES cal excitability and low frequency tends to phasic stimulators are simpler in design The double-cone coil is similar in ge- decrease it, and longer durations of stimu- and inadequate for generating the repeti- ometry to the figure-8 coil but rather than lus may increase the duration of after ef- tive pulses required for therapeutic use. being flat, each side of the coil is rotated fects; the exact mechanisms of all the above Biphasic stimulators enable shorter in- to form an angle. The coil is able to create are not completely understood.5 terpulse periods by using nonpolarized higher intensities of electric field at depth capacitors, allowing energy to be returned than is possible with a standard figure-8 THETA BURSTS to the capacitor during each pulse. These coil, with some studies showing it to be Theta burst stimulation (TBS) proto- stimulators have become more widely capable of stimulating the leg motor area, cols consist of very high-frequency (ap- used, offering pulse repetition rates of up located 30 to 40 mm below the surface proximately 2500 Hz) pulses delivered in to 100 Hz13 as required for TBS. of the scalp.20,21 Roth et al.22 estimate the 100-Hz bursts at 5-Hz intervals, which is stimulation threshold of neurons to be 20 consistent with theta rhythm as measured EARLY TMS COIL DESIGNS to 60 V/m, requiring 30% to 50% of the on electroencephalography.12 TBS proto- Following the first demonstration of maximum output achievable with a com- cols can be divided into two main catego- noninvasive stimulation of the human mo- mon commercial magnetic stimulator, ries, intermittent and continuous, with the tor cortex by Barker et al.14 in 1985, TMS when used with the double-cone coil. It effects being excitatory and inhibitory, re- stimulator coils were predominantly of flat is indicated that attempting stimulation spectively. Intermittent TBS is defined as circular type. The greatest electric field is of deeper-lying regions can be painful 1840 ms of stimulation repeated every 10 induced directly below the coil windings, because of the high-intensity field being

039#()!42)#!..!,3s6OL .O 281 CME Copyright 2014 SLACK Inc. induced in higher cortical areas and the commonly used coil designs are used for coil designs was calculated using the possible stimulation of facial muscles. A stimulation of deep brain regions, the in- method proposed by Eaton,34 assuming a drawback of the geometry of the double- tensity of field that is required stimulates current discharge of 10 kA in 100 ␮sec, cone coil is that it produces larger field in- cortical regions and also facial nerves to resulting in an optimized design for deep tensities at the sides of the head. The field an extent that can cause pain.22 However, brain stimulation. Crucially, Roth et al.22 in these regions can approach 50% of the the ability to stimulate deep brain regions identified the effect of coil orientation on maximum field produced below the coil noninvasively could lead to the develop- induced electric field, stating that coil ele- center when stimulator output is 150%.3 ment of various therapeutic applications ments that are perpendicular to the brain In this case, the field below the side loops for neurobehavioral disorders37 and non- tissue surface create an accumulation of is theoretically capable of stimulating invasive treatment of tremor arising from surface charge, which adversely effects brain tissue. Therefore, care must be taken Parkinson’s disease and dystonia in place or cancels the perpendicular component when using the double-cone coil to ensure of deep brain stimulation where elec- of the induced electric field. For this rea- that only brain regions below the cen- trodes are inserted into the brain. When son, the H-Coil minimizes the presence of ter of the coil are affected. Although the designing stimulator coils for this pur- coil elements not tangential to the tissue double-cone coil will improve the depth at pose, various factors must be considered. surface. Zangen et al.40 report on use of which stimulation can be achieved, it will The stimulation threshold of neurons a modified H-Coil for stimulation of the also increase the volume of tissue that is needs to be fully understood to ensure abductor pollicis brevis (APB) area of stimulated. new coil designs are capable of achiev- the motor cortex to test the efficacy of the To reduce the field intensity away ing stimulation where desired. Conflict- coil. The motor threshold was measured from the coil center in figure-8 coils, ing values of stimulation threshold can be in patients as the H-Coil was progres- double-butterfly coils and later, eccentri- found in the literature,22,38 with values of sively moved away from the surface of the cally wound coils have been proposed.23,24 required intensity ranging from 20 to 100 head. The intensity that was required for Other methods for manipulating the field V/m. Variations in this value are likely to stimulation of the APB at various distanc- produced by figure-8 coils have included occur due to the alignment of the neurons es from the scalp using the H-Coil and a the use of a conductive shielding plate25 and the overlying gyral folding pattern. figure-8 coil were compared. As distance and “active” shielding by magnetic fields The limitations of the available magnetic from the scalp increases, the stimulator produced by secondary coils.26 Layering stimulators must also be taken into ac- output that is required to achieve stimula- multiple figure-8 coils has also been pro- count, meaning new coils must conform tion was shown to be reduced when us- posed.27 To achieve an effective “sham” to existing inductance values, typically in ing the H-Coil. When using the maximum coil for use in clinical studies, coils with the range of 15 to 25 ␮H. stimulator output available, the figure-8 the ability to engage a reverse-current The Halo coil, a large circular coil coil was able to stimulate the APB at a dis- mode have been developed,28 provid- capable of being placed over the head, tance of 20 mm from the scalp, whereas ing the sensation of stimulation without was developed to increase the magnetic the H-Coil was able to stimulate the APB producing a field of sufficient intensity field at depth in the brain when used to- at a distance of 55 mm. A comprehensive for neuronal activation. Many TMS coils gether with an existing circular or figure-8 comparison of the H-Coil and a standard rely solely on the magnetic field produced coil.39 The Halo coil has been shown to figure-8 coil is provided by Fadini et al., 41 by the current carrying conductor (typi- provide less decay of field as a function indicating “no advantage of this coil with cally copper) in the coils to produce the of distance than a figure-8 coil. Magnetic regard to depth of stimulation in compari- stimulating field. However, coils making field measurements revealed that the Halo son to the figure-of-eight coil,” but also use of ferromagnetic iron cores have been coil in combination with a circular coil noting that more study is indicated. proposed in coils of varying designs and increases the magnetic field strength by sizes29-32 and used in widely used com- 10% at a depth of 20 mm and by 50% at CONCLUSION mercial systems.33 a depth of 50 mm, when compared to the Although the practice of using chang- circular coil energized alone. Roth et al.22 ing magnetic fields to stimulate the brain COILS FOR DEEP TMS have also proposed a coil design, termed has been taking place for many years, The ability to noninvasively stimulate the Hesed Coil (H-Coil), for the stimu- using this phenomenon to modulate the deep brain regions has proved challeng- lation of deep brain regions, identifying brain and provide therapy is a practice ing as the intensity of electric field in the that previously used coils mainly stimu- still very much in infancy. The technology brain decays rapidly as a function of dis- late the cortical brain regions only. The to do so is rapidly evolving and proliferat- tance from the stimulator coil.18,19,34-36 If electric field induced by several of these ing, and it now will behoove psychiatrists

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