Transcranial magnetic stimulation (TMS) is a safe, noninvasive neuromodulation procedure that uses high-strength pulsed magnetic fields to induce a depolarizing current in a localized area of the cerebral cortex. Introduced into research in 1985, TMS was first used experimentally to treat depression in the mid-1990s. In 2008, the U.S. Food and Drug Administration (FDA) cleared a specific TMS device for use in treating patients with unipolar major depression who had failed to respond to conventional antidepressant medication treatment. TMS represents an important breakthrough in the treatment of depression for a variety of reasons, including the following: TMS is effective for patients who fail to respond to antidepressant medication. Unlike electroconvulsive therapy (ECT), TMS is an office-based procedure that requires no anesthesia or sedation. Unlike ECT, TMS causes no cognitive side effects. Unlike medications, TMS causes no systemic side effects such as weight gain or sexual dysfunction. Unlike medications, which are prone to patient error and nonadherence, TMS is an observed procedure during which the clinician can ensure proper administration. In this chapter, I provide an overview of TMS. An explanation of the basic principles underlying the procedure is followed by a brief history of the development of TMS as a treatment for depression, a general overview of how different TMS parameters affect brain function, and a review of the efficacy of TMS in the treatment of depression, including controlled trials and naturalistic observational studies. A typical course of treatment is described along with a more detailed explanation of standard stimulus parameters and variations that may be employed. The chapter concludes with a discussion about the mechanism of action of TMS. The fundamental concepts underlying TMS have been understood for over a century. Electricity and magnetism are two aspects of the same phenomenon. Every electrical current creates a magnetic field, and a magnetic field can create an electrical field in the surrounding space. TMS is a clinical application of Faraday’s law of induction, which states that a moving magnetic field causes an electrical current to flow in a nearby conductor (Faraday 1831/1965). In the case of TMS, the electrical conductor is the human brain (Figure 1–1). Thus, TMS may be considered a form of brain electrical stimulation without the use of electrodes. Figure 1–1. A moving magnetic field causes electrical current to flow in nearby neural tissue. Although not depicted in this illustration, the transcranial magnetic stimulation coil must be in direct contact with the patient’s scalp to produce an electrical field strong enough to cause depolarization. All TMS devices share the same basic elements (Figure 1–2). A capacitor is used to store electricity. A thyristor switch is used to precisely control the flow of current. Rapidly turning the current on and off produces a time-varying or moving magnetic field as the current flows through a coiled cable (Davey and Epstein 2000). Peak voltages are typically on the order of 2,000 V, and currents are around 10,000 A. Figure 1–2. Schematic illustration of basic transcranial magnetic stimulation circuit design: capacitor, thyristor switch, and stimulating coil. Ancillary circuits include those for temperature monitoring and for setting the frequency and intensity of pulses. C=capacitor; D=diode; R=resistance; S=switch; SC=stimulating coil; T=thyristor; V=charging circuit. The size and shape of the TMS coil determine the size and shape of the induced electrical field. TMS coils come in many shapes. The simplest, and historically the first to be used, is a circle measuring about 8–15 cm in diameter. Such round coils can stimulate a large area of the brain but cannot be focused. Two round coils placed side by side form what is known as a figure-eight or butterfly coil. This design allows stimulation at a limited and clearly defined location. For this reason, figure-eight coils have become the most widely used for research and therapeutic purposes (see Figure 10–1 in Chapter 10, “Current FDA-Cleared TMS Systems and Future Innovations in TMS Therapy”). Depth of penetration is limited by the laws of physics because magnetic field strength decreases exponentially as a function of distance. The magnetic field strength of TMS is approximately 1.5–2.5 teslas at the surface of the coil. This is about the same strength as a first-generation magnetic resonance imaging (MRI) machine and more than 30,000 times stronger than the earth’s magnetic field, yet it is barely detectable only a few centimeters away. Most figure-eight coils activate a cortical area of approximately 2–3 cm and to a depth of approximately 2–3 cm (Deng et al. 2013). A newer type of coil, known as the Hesed or H coil, uses multiple coil windings to achieve greater depth of penetration but with less precise focus. Basically, the deeper the penetration, the more diffuse the electrical field (see Figure 10–2 in Chapter 10). Figure 1–3 shows an example of a TMS delivery system. Chapter 10 provides an in-depth discussion of several FDA-approved TMS delivery systems. Figure 1–3. NeuroStar TMS Therapy System. Source. Image courtesy of Neuronetics, Inc. The first magnetic nerve stimulator was built by Anthony Barker and colleagues at the University of Sheffield in 1985 (Barker et al. 1985). Although this was originally intended for peripheral nerve stimulation, it was quickly discovered that placing the coil over the motor cortex allowed for quick and easy, noninvasive stimulation of upper motor neurons. Early TMS research focused primarily on motor cortex excitability and plasticity using single or paired pulses of TMS. These early experiments showed that magnetic stimulation could produce changes in cortical excitability lasting for a few seconds or up to several minutes (Uozumi et al. 1991). Advances in electronics soon allowed for the development of repetitive TMS, in which multiple volleys or trains of pulses at frequencies between 1 Hz and 50 Hz can be administered in rapid succession. (In this volume, TMS and repetitive TMS will be used interchangeably.) This technical development allowed magnetic stimulation to induce changes in cortical excitability lasting for a few minutes or up to several hours or longer. These aftereffects are thought to be due to long-term potentiation and long-term depression mechanisms. Pioneering studies on motor cortex showed that TMS delivered at low frequencies (≤1 Hz) for several minutes was able to reduce the amplitude of motor evoked potentials, reflecting a decrease in cortical excitability (Chen et al. 1997). On the other hand, TMS delivered at higher frequencies (≥5 Hz) increased motor evoked potentials, reflecting an increase in cortical excitability (Pascual-Leone et al. 1994). This research yielded important insights, occurring at a time when functional brain imaging studies began to shed light on the pathophysiology of psychiatric disorders. One of the most important findings from this research was decreased left prefrontal activity in major depression. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies demonstrated a correlation between the depressed state and reduced regional cerebral metabolic rate of glucose uptake and reduced regional cerebral blood flow in the left dorsolateral prefrontal cortex (DLPFC) (Mayberg 2003). Increased activity of the right prefrontal region was also demonstrated (Drevets et al. 2008). Further, functional MRI and PET studies correlated depressive behavior with hypermetabolism of the subgenual cingulate cortex and amygdala (Savitz and Drevets 2009a) and hypometabolism of the dorsal prefrontal cortex and striatal regions (Ressler and Mayberg 2007), thus defining a “depression circuit” (Figure 1–4). These developments allowed researchers to investigate the potential use of TMS as a treatment for depression by “normalizing” the activity of the left DLPFC using high-frequency, excitatory TMS (Schutter 2009) and reducing the activity of the right DLPFC using low-frequency, inhibitory TMS to restore the interhemispheric balance between left and right DLPFC activity (Schutter 2010). Figure 1–4. Depression circuit in the brain. Left-sided lateral view of the brain, indicating the key structures and functions implicated in the pathophysiology of major depressive disorder: dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (mPFC)—executive function, regulation of emotion and assessment of consequences in decision making, and extensive connections with anterior cingulate cortex (ACC) and limbic areas, including hippocampus and amygdala; orbitofrontal cortex (OFC)—integration of multimodal stimuli and assessment of stimulus value and/or reward; ventrolateral prefrontal cortex (VLPFC)—attentional control; ACC—extensive connections with brain structures implicated in emotional behavior, key part of an extended network in emotional processing and autonomic regulation; thalamus—sensory relay, extensive connections with limbic system and mood-related circuitry; hypothalamus—linking of nervous system to endocrine system; synthesizing and secreting of neurohormones, including corticotropin releasing factor, key structure in controlling hypothalamic-pituitary adrenal axis (HPA) function; amygdala—evaluation of experience/stimuli with strong emotional valence and acquisition and expression of emotionally laden memories; nucleus accumbens—reward, pleasure, and pain avoidance; and hippocampus—learning, memory, and cognition, site of adult neurogenesis, and negative regulation of HPA axis. In a clinical context, TMS is usually described in terms of four separate but interrelated parameters: Location—brain region stimulated Intensity—magnetic field strength (induced electrical field strength) Frequency—number of pulses per second and frequency of treatment sessions Duration—number of pulses per treatment session and total number of treatment sessions Together, these parameters form the basis of TMS dosage and administration. The effects of TMS depend on which brain region is stimulated. For example, stimulating the motor cortex produces an immediately observable response in the form of a contralateral skeletal muscle contraction. Stimulating the occipital cortex can produce the subjective experience of flashing lights (phosphenes). Stimulating Broca’s area can cause momentary speech arrest (Pascual-Leone et al. 1991). Stimulating most other cortical areas, however, produces no immediately observable or subjective response. This is clearly the case with TMS treatment for depression, in that clinical results are typically seen only after several weeks of stimulation. The most common stimulus target for treating depression Magnetic field strength must be strong enough to induce an electrical field capable of causing depolarization. In routine clinical practice, the intensity of the transcranial magnetic stimulus is usually expressed as a percentage of the patient’s motor threshold (MT), which is defined as the average minimum stimulus required to produce a visible muscle movement (or evoked motor potential) 50% of the time. For TMS treatment of depression, MT is usually determined by observing contractions of the right abductor pollicis brevis muscle. The most common stimulus intensity for treating The speed, or the number of magnetic pulses per second, determines the effect on the underlying brain tissue being stimulated. Slow pulses of 1 Hz or less decrease the excitability of the stimulus target. Frequencies greater than 1 Hz increase the excitability of the stimulus target. The most common stimulus frequency for treating depression is 10 Hz. Early studies of TMS treatment for depression typically involved the administration of several dozen to a few hundred pulses per treatment session. Treatment courses lasted anywhere from a few days to several weeks. Over time, the total number of pulses per treatment session and the total number of sessions in a single course of treatment steadily increased. TMS treatment for depression typically involves treatment 5 days/week, Monday through Friday. Treatment sessions generally last 20–45 minutes. On average, 30 or more treatments consisting of 3,000 or more pulses per session are needed for maximum therapeutic benefit. Evidence for the clinical efficacy of TMS in the treatment of depression includes more than 30 sham-controlled clinical studies involving over 2,000 patients. Aggregate data have been examined in more than 15 meta-analyses and qualitative reviews, providing a consistent, comprehensive, and replicated literature base. FDA clearance of TMS was based on a specific treatment protocol delivered by a specific device in a large (N=301 patients), multisite (N=23), randomized sham-controlled trial (O’Reardon et al. 2007). Patients in this study had failed to respond to at least one and no more than four antidepressant medications and were medication free at the time of the study. When this trial was designed, it was not clear how long patients needed to be treated. Many previous studies administered treatment for only 2 weeks, which is much less than is usually needed for medications (typically 6–8 weeks) or ECT (2–4 weeks) to take effect. Also unclear was the overall intensity of stimulation required. Many previous studies used stimuli of 90%–110% of MT, sometimes administering only a few hundred pulses per treatment session. In the O’Reardon et al. (2007) study, treatment was provided 5 days/week (Monday through Friday) for 4–6 weeks, followed by a 3-week tapering phase. Patients received up to 36 sessions of TMS therapy in 9 weeks. The treatment protocol used high-intensity, high-frequency stimulation of 10 Hz at 120% of MT delivered over the left DLPFC with 75 four-second-long pulse trains, totaling 3,000 pulses per treatment session. This duration and intensity of stimulation was unprecedented at the time. Active TMS was found to be significantly superior to sham TMS based on patients’ scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the 17- and 24-item Hamilton Depression Rating Scale (HDRS-17 and HDRS-24) at weeks 4 and 6. Response rates were significantly higher with active TMS than sham TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS than sham TMS at week 6 and were significant on the MADRS and HDRS-24 (but not the HDRS-17). Active TMS was well tolerated, with a low dropout rate for adverse events (4.5%), which were generally mild and limited to transient scalp discomfort or pain (O’Reardon et al. 2007). Patients who failed to benefit from at least 4 weeks of randomized treatment assignment in the controlled trial (either active or sham) were eligible to participate in an open-label extension trial, although patients and investigators remained blinded to prior assignment at the time of entry into this phase (Avery et al. 2008). For those patients who received sham TMS in the preceding randomized controlled trial (N=85), the mean reduction in MADRS scores after 6 weeks of open-label active TMS was 17.0. Furthermore, based on the MADRS, at 6 weeks, 36 of these patients (42.4%) achieved response and 17 patients (20.0%) achieved remission (i.e., MADRS score <10). For those patients who received but did not respond to active TMS in the preceding randomized controlled trial (N=73), the mean reduction in MADRS scores was 12.5, and response and remission rates were 26.0% and 11.0%, respectively. An independent (nonindustry) study sponsored by the National Institute of Mental Health (NIMH)—Optimization of TMS for Depression (OPT-TMS)—corroborated the results of the FDA registration study. This NIMH study used the same device and same treatment parameters as the FDA study but with several methodological improvements, including MRI adjustment for coil placement, an adaptive flexible duration of treatment, an improved sham device that better mimicked the sensory experience of TMS, and continuous assessment of outcome evaluator reliability relative to a masked external expert rater (George et al. 2010). High-intensity TMS for at least 3 weeks was found to be significantly more likely than sham TMS to induce remission (the primary end point) in antidepressant medication–free patients with moderately treatment-resistant unipolar major depressive disorder. It should be noted that the level of treatment resistance in this study was higher than in the FDA registration study. The coil (H coil) used in deep TMS is able to modulate cortical excitability up to a maximum depth of 6 cm and is therefore able not only to modulate the activity of the cerebral cortex but also the activity of deeper neural circuits (Bersani et al. 2013). The Brainsway Deep TMS System H1 coil device was cleared by the FDA in 2013. The intent-to-treat sample included 212 patients at 20 sites in four different countries. All patients had failed to respond to trials of one to four antidepressant medications during the current episode and were randomly assigned to receive either active deep TMS or sham treatment. Patients, treaters, and raters were fully blinded. A total of 181 patients completed the study per protocol. Acute treatment consisted of five sessions per week for 4 weeks, followed by a continuation phase of twice-weekly treatment for 12 more weeks. The stimulation site was the left DLPFC, although broader stimulation is likely with the H1 coil. Stimulation parameters were MT of 120%, frequency of 18 Hz, train duration of 2 seconds, intertrain interval of 20 seconds, and 55 trains per session, for a total of 1,980 pulses over 20 minutes (Levkovitz et al. 2015). The primary end point in the Levkovitz et al. (2015) study was the change in total score on the 21-item Hamilton Depression Rating Scale (HDRS-21) from baseline to week 5. The secondary efficacy end points were response and remission rates at week 5. Response was defined as a reduction of at least 50% in the total HDRS-21 score compared with baseline, and remission was defined by a total HDRS-21 score that was lower than 10. In the intent-to-treat sample, the difference of –2.23 points (95% confidence interval [CI]: –4.54, 0.07) between the slopes across 5 weeks fell just short of reaching statistical significance (P=0.0578). However, the study results were analyzed for a subset of patients who received the prescribed stimulation protocol at 120% of MT (n=181; 89 in the deep TMS sample and 92 in the sham sample). In this subsample of patients, the difference of –3.11 points (95% CI: –5.40, –0.83) between the slopes was statistically significant (P=0.008), with an effect size of 0.76. In terms of the secondary outcome measures, at week 5, the response rates (prescribed stimulation protocol set) were 38.4% for active treatment versus 21.4% for sham TMS (P=0.0138), and remission rates (prescribed stimulation protocol set) were 32.6% for active treatment versus 14.6% for sham TMS (P=0.0051). At week 16, the response rates were 44.3% for active treatment versus 25.6% for sham TMS (P=0.0086), and remission rates were 31.8% for active treatment versus 22.2% for sham TMS (P=0.1492). Although these response and remission rates are higher than in the previously discussed FDA registration trial and OPT-TMS study, the study populations were different, as were the primary outcome measures. Direct comparisons of deep TMS versus standard figure-eight coil TMS have yet to be done. In addition to the randomized controlled studies described in the previous section, several multisite, naturalistic observational studies have examined the safety and long-term effectiveness of TMS in clinical populations. These latter studies are important because they more accurately reflect the administration of TMS in a “real-world” setting. For example, both the FDA registration study and the OPT-TMS study excluded patients with Axis I disorders other than major depression (except for simple phobia and nicotine addiction). In typical clinical practice, however, many patients receiving TMS have comorbid psychiatric illness such as an eating disorder or posttraumatic stress disorder or a history of psychosis. Similarly, in both the FDA registration study and the OPT-TMS study, patients were required to be medication free for 1 week prior to the start of the study. This is almost never the case in the real world, where virtually all patients with depression are taking one or more psychotropic medications, often from different classes. Carpenter et al. (2012) looked at outcomes for 307 patients treated at 42 clinical TMS practice sites in the United States. The majority of patients were treated using the standard FDA-approved protocol associated with the NeuroStar device (Figure 1–3). The clinician-assessed response rate based on the Clinical Global Impression—Severity of Illness Scale (CGI-S) was 58.0% and the remission rate was 37.1%. Patient-reported response rates ranged from 56.4% to 41.5%, and remission rates ranged from 28.7% to 26.5%, based on the 9-item Patient Health Questionnaire (PHQ-9) and Inventory of Depressive Symptomatology—Self Report (IDS-SR), respectively. Overall, these outcomes were similar to those seen in research populations. Functional status and quality-of-life outcomes were also assessed in this same group of 307 patients (Janicak et al. 2013). Following acute TMS treatment, statistically significant improvement was observed in functional status on a broad range of mental health and physical health domains, based on the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Similarly, statistically significant improvement in patient-reported quality of life was observed on all domains of the EuroQol 5-Dimensions questionnaire (EQ-5D) and on the General Health Perception and Health Index subscale scores. Improvement on these measures was observed across the entire range of baseline depression symptom severity, demonstrating that TMS as administered in routine clinical practice settings produces statistically and clinically meaningful improvements in patient-reported quality of life and functional status. The durability of TMS effect following acute treatment has been demonstrated in several studies both with and without maintenance antidepressant medication. In general, these studies demonstrate high durability for acute TMS benefits. Details regarding long-term outcome studies are provided in Chapter 6, “Managing Patients After Transcranial Magnetic Stimulation.” More than a dozen meta-analyses of TMS treatment of depression have been published. Schutter (2009) evaluated 30 double-blind, sham-controlled studies involving 1,164 patients and found that high-frequency TMS over the left DLPFC was superior to sham TMS, with an effect size comparable to that of commercially available antidepressant drugs. In a larger study, Slotema et al. (2010) examined 34 sham-controlled studies involving 1,383 patients; the authors concluded that TMS is effective in treating depression and has a mild side-effect profile. In a more recent meta-analysis, Gaynes et al. (2014) concluded that TMS is a reasonable and effective consideration for patients with major depression who have had at least two previous antidepressant treatment failures and that patients receiving TMS were at least five times as likely to achieve remission as patients receiving sham TMS. The most common form of TMS treatment for depression involves high-frequency stimulation over the left DLPFC. A frequency of 10 Hz was used in the pivotal trials leading to FDA clearance of TMS in the United States and is the most commonly used frequency for figure-eight coil TMS. The Brainsway H1 coil stimulates at a frequency of 18 Hz. There is also a body of evidence to support the efficacy of low-frequency 1-Hz stimulation over the right DLPFC (Isenberg et al. 2005; Pallanti et al. 2010), and sequential administration of both left-sided high-frequency TMS and right-sided low-frequency TMS in the same treatment session has been used to maximize treatment efficacy (Fitzgerald et al. 2006). A recent systematic review and network meta-analysis involving 81 studies with 4,233 patients found few differences in clinical efficacy between these different modalities (Brunoni et al. 2017). Theta-burst stimulation (TBS) is a modified form of TMS in which a three-pulse 50-Hz burst is applied at 5 Hz (every 200 milliseconds) representing the theta rhythm. In intermittent TBS, a 2-second train of TBS is delivered every 10 seconds for 600 pulses in total. Continuous TBS involves an uninterrupted 40-second train of TBS amounting to a total of 600 pulses (Daskalakis 2014). Intermittent TBS produces long-term potentiation-like (excitatory) effects, whereas continuous TBS produces a long-term depression-like reduction of cortical excitability. These neuroplastic changes may occur within seconds (Huang et al. 2005). Intermittent TBS is thought to increase and continuous TBS is thought to decrease the postsynaptic concentration of calcium ions, an important factor in enhancing synaptic plasticity (Huang et al. 2011). Intermittent TBS applied to the left DLPFC or a combination of intermittent TBS applied to the left DLPFC plus continuous TBS applied to the right DLPFC has been shown to be effective in treatment-resistant depression (Li et al. 2014). TBS is still considered to be investigational. Early TMS studies used stimulus intensities of 80%–90% of MT and generated mixed results. It eventually became clear that suprathreshold stimulation at 110%–120% of MT was necessary to produce antidepressant effects. MT is typically expressed as a percentage of the total output of the specific TMS device being used. MT is relatively stable over time and usually needs to be determined only once, at the start of treatment. Several methods may be used to determine the correct stimulation site. The most commonly used method for determining the coil placement site involves isolating the motor cortex area corresponding to the abductor pollicis brevis muscle and moving the coil 5 cm anteriorly. This so-called 5-cm rule has been used since the 1990s and was used in the pivotal trial leading to FDA clearance. This proves that the method can be used to administer effective treatment. Studies have shown, however, that this method may result in accurate placement only about 70% of the time (Johnson et al. 2013), raising the question of whether more robust response and remission rates might be seen if coil placement could be better ensured. The chief drawback to the 5-cm rule is that it fails to account for differences in head size and may result in the coil being placed too far posteriorly or medially. One study estimated that the 5-cm rule would localize to the premotor cortex for 32% of patients, with variable positioning for the rest (Herwig et al. 2001). Apart from the possibility of providing ineffective treatment, seizure risk may also be increased if the coil is too close to the motor cortex. Because of these concerns, some clinicians routinely position the coil forward by 1 cm or more, although moving the coil too far forward increases the likelihood of ocular pain or facial discomfort (due to stimulation of the trigeminal nerve) during treatment. The most accurate method of treatment site location involves the use of a neuronavigation system composed of a reference MRI brain scan, stereotactic sensors, and sophisticated software to guide coil placement (Schönfeldt-Lecuona et al. 2010). It is worth noting that this method was used for about one-third of patients in the OPT-TMS trial. The chief drawbacks are the added cost and the fact that most systems are cumbersome, are difficult to use, and require a considerable amount of staff training. For these reasons, neuronavigation is rarely used outside of academic research settings where it may be essential for other TMS applications, such as treatment for stroke. More accurate than the 5-cm rule and of comparable accuracy to neuronavigation is the use of the International 10-20 System of electroencephalogram electrode placement. Using this method, the target is the F3 electroencephalogram site, which corresponds to the DLPFC. Normally, this is a derived location obtained only after first taking a series of painstaking measurements. Beam et al. (2009) at the Medical University of South Carolina developed a streamlined method of locating F3 that requires only three simple measurements: tragus to tragus, nasion to inion, and head circumference. Entering these measurements into an equation yields a set of coordinates that can be easily marked on the patient’s scalp, directly corresponding to F3. This method has been compared with neuronavigation and found comparable to within 3 mm (Mir-Moghtadaei et al. 2015). Table 1–1 summarizes the treatment parameters that are commonly used for treating depression. Table 1–1. Transcranial magnetic stimulation: common stimulus parameters for major depressive disorder Parameter Comment Coil location Most often: left DLPFC Less often: right DLPFC MT Lowest stimulus intensity over primary motor cortex to produce contraction of the abductor pollicis brevis muscle, assessed visually or by electromyography Stimulus pulse Intensity 90%–120% of MT Frequency HF 10–20 Hz; LF ≤1 Hz; TBS 3 pulses at 50 Hz Pulse train duration HF 2–4 seconds; LF 5–26 minutes; TBS 40–90 seconds Pulse train interval HF 10–28 seconds; LF 0 seconds Number of pulses HF: per session 1,500–6,000 per course Up to 216,000 LF: per session 900–1,600 per course Up to 57,600 Note. DLPFC=dorsolateral prefrontal cortex; HF=high frequency; LF=low frequency; MT=motor threshold; TBS=theta-burst stimulation. Source. Adapted from Janicak and Dokucu 2015. MT determination and coil placement are essential elements of correct TMS dosage and must be determined by the treating physician. Responsibility cannot be delegated to a technician or other assistant no matter how well trained. These and other best practice guidelines are contained in the “Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder” (Perera et al. 2016). A typical course of TMS can last 6 weeks or more. Most patients require 30–36 treatments to achieve maximum therapeutic benefit. Treatments are usually administered 5 days/week, but at least two studies have shown that overall outcome is the same when treatments are administered 3 days/week in a treatment course that is correspondingly longer (Galletly et al. 2012; Turnier-Shea et al. 2006). There is no evidence that administering treatment 7 days/week hastens recovery or produces a better outcome. One study suggests that the overall length of treatment may be shortened by administering multiple treatments over several days, without any increase in risk (Holtzheimer et al. 2010). Another study found that three TMS treatments per day over the course of 3 days brought about a rapid decrease in suicidal ideation (George et al. 2014). A typical treatment session lasts 20–45 minutes depending on the treatment parameters used. Most patients adapt quickly to the stimulus sensation, and premature discontinuation of treatment is uncommon. The structure provided by daily treatment and the interpersonal context of treatment may have therapeutic value for some patients and are worthy of further study. Improvement occurs gradually and is similar to the time course seen with antidepressant medication. Most patients notice improvement between 15 and 20 treatments, although earlier and later responses may occur. Core somatic symptoms typically improve before subjective sadness and other psychological symptoms do, and family or friends may notice changes first. Interestingly, many patients report a change in visual perception and find that colors appear more vivid. Many also report improved clarity of thinking and improved memory. Regular follow-up by the treating physician is essential. Standardized rating scales such as the PHQ-9 and Quick Inventory of Depressive Symptomatology (QIDS) provide quantifiable measures of symptom severity, and their use is routinely required by many insurance plans to justify the ongoing need for treatment. Although a course of TMS may sometimes end abruptly, more often it is tapered over several weeks. Typically, a course of treatment will consist of about 25–30 treatments administered 5 days/week followed by a tapering phase of three treatments for 1 week, two treatments the next week, and one treatment the final week. Since the monoamine hypothesis was first proposed more than 50 years ago (Schildkraut 1965), theories about the pathogenesis of depression and the mechanism of action of antidepressant medications have focused on the level of cell-to-cell interaction and synaptic transmission, with particular attention to serotonin, dopamine, and norepinephrine. Most antidepressant medications increase extracellular levels of these monoamine neurotransmitters and thereby alter synaptic signaling (Tanti and Belzung 2010). Animal experiments have shown that prefrontal TMS affects neurotransmitter concentrations in a variety of brain regions distant from the stimulation site, including serotonin and dopamine in the prefrontal cortex, striatum, and hippocampus (Gur et al. 2000; Pogarell et al. 2007). Like antidepressants, TMS appears to normalize the function of the hypothalamic-pituitary-adrenal axis and appears to decrease corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) (Keck et al. 2001). TMS also appears to exert a neuroprotective effect by decreasing oxidative stress (Post et al. 1999) and by increasing the level of brain-derived neurotrophic factor in the dentate gyrus of the hippocampus (Tardito et al. 2006). Evidence suggests that enhanced neuroplasticity is a common feature of all antidepressant medications, as well as of neuromodulation treatments such as TMS (Krishnan and Nestler 2010; Racagni and Popoli 2008). In contrast to medication, however, TMS is delivered at a very different level of brain organization. Rather than targeting synaptic proteins, TMS is applied to cortical circuits. Functional brain imaging has shown that depression is marked by dysfunction in a number of cortical regions, such as the DLPFC and anterior cingulate cortex, as well as in deep gray matter structures, including the amygdala, nucleus accumbens, and thalamic and hypothalamic nuclei. Depression is increasingly understood as a disorder of connectivity in neural networks linking these regions (Greicius et al. 2007; Leuchter et al. 2012). Many of the mood and neurovegetative symptoms, as well as deficits in cognition and memory, are thought to arise from dysfunction in networks linking cortical and subcortical gray structures (Ottowitz et al. 2002; Savitz and Drevets 2009b). Thus, major depressive disorder has been conceptualized as a syndrome of “thalamocortical dysrhythmia,” marked by persistent resonance of rhythmic thalamocortical activity (Leuchter et al. 2015). TMS may directly modulate this rhythmic thalamocortical activity in a top-down fashion at the level of large-scale networks to influence neuronal firing rates, firing patterns, and other processes at the cellular level. Conversely, medications would appear to act in a bottom-up fashion by inducing changes at the level of the synapse followed by changes in neuronal firing rates and patterns, eventually affecting network activity (Leuchter et al. 2015). TMS represents a major advance in noninvasive therapeutic neuromodulation with proven efficacy in the treatment of major depressive disorder. Its safety and benign side-effect profile make it a viable treatment alternative for patients who do not respond to standard treatments. Modifications in TMS technique and improvements in TMS technology, including the development of new stimulation coils, may further enhance clinical efficacy. Research also suggests that other cortical sites, such as the ventromedial prefrontal cortex, may eventually become therapeutic targets. While the mechanism of action of TMS is not fully understood, evidence suggests that its therapeutic effects are the result of neuroplastic changes in thalamocortical circuits involved in the expression of core symptoms of major depression. These findings, together with those derived from other lines of research, such as neuroimaging, may shed light on the pathophysiology and circuit dysfunction associated with other neuropsychiatric disorders perhaps leading to clinical applications beyond major depressive disorder. KEY CLINICAL POINTS • TMS is an effective treatment for patients who fail to respond to antidepressant medication and psychotherapy. • The most common stimulus target for treating depression is the left dorsolateral prefrontal cortex, the most common stimulus intensity is 120% of the patient’s motor threshold, and the most common frequency is 10 Hz. TMS treatment for depression typically involves daily treatment sessions, Monday through Friday, lasting 20–45 minutes. • Clinical improvement may be seen in 2–3 weeks but typically requires 30 or more treatments over 4–6 weeks. References Avery DH, Isenberg KE, Sampson SM, et al: Transcranial magnetic stimulation in the acute treatment of major depressive disorder: clinical response in an open-label extension trial. J Clin Psychiatry 69(3):441–451, 2008 18294022 Barker AT, Jalinous R, Freeston IL: Non-invasive magnetic stimulation of human motor cortex. 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Aust NZJ Psychiatry 40(9):759–763, 2006 16911750 Uozumi T, Tsuji S, Murai Y: Motor potentials evoked by magnetic stimulation of the motor cortex in normal subjects and patients with motor disorders. Electroencephalogr Clin Neurophysiol 81(4):251–256, 1991 1714818 ______________ Note. Although TMS and repetitive TMS are technically different, in this book the abbreviation TMS is used predominantly.
1
Transcranial Magnetic
Stimulation Therapy for
Treatment-Resistant
Depression
Basic Principles and Technology of TMS
Development of TMS
General Overview of TMS Parameters
LOCATION
is the left DLPFC.
INTENSITY
depression is 120% of the patient’s motor threshold.
FREQUENCY
DURATION
Efficacy of TMS Treatment for Depression
FDA REGISTRATION STUDY
OPTIMIZATION OF TMS FOR DEPRESSION STUDY
DEEP TMS STUDY
Naturalistic Observational Studies
OVERALL EFFECTIVENESS
QUALITY–OF-LIFE MEASURES
DURABILITY OF EFFECT
META-ANALYTIC STUDIES
TMS Treatment Parameters for Depression
STIMULUS FREQUENCY
STIMULUS INTENSITY
TREATMENT SITE LOCATION
Five-Centimeter Rule
Neuronavigation
Electroencephalogram F3 Method
Typical Course of Treatment
MOTOR THRESHOLD DETERMINATION AND INITIAL TREATMENT
ACUTE TREATMENT PHASE
TAPERING PHASE
Mechanism of Action
Conclusion
Related posts:
Transcranial Magnetic Stimulation and Other Neuromodulation Therapies
Clinical Applications and Patient Selection
Transcranial Magnetic Stimulation for the Treatment of Other Mood Disorders
Transcranial Magnetic Stimulation for Disorders Other Than Depression
Transcranial Magnetic Stimulation and Psychotherapy
Current FDA-Cleared TMS Systems and Future Innovations in TMS Therapy
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