Paul E. Holtzheimer and William M. McDonald
The first studies of transcranial magnetic stimulation (TMS) were performed in 1985 by Anthony Barker and his colleagues at the Royal Hallamshire Hospital in Sheffield, England. These studies demonstrated that TMS could induce muscle movements in the hand when applied to the cortical motor strip (Barker, Jalinous, & Freeston, 1985). These early studies provided support for a noninvasive method that could focally stimulate underlying cortical pathways and were the foundation for research into the stimulation of cortical pathways involved in a number of disease processes. Barker’s original research was based on single-pulse TMS where a single stimulus was delivered to a specific brain region. Expanding on this, the technology developed to allow a device to deliver multiple stimuli over a short period of time, that is, repetitive TMS (rTMS). rTMS was shown to have lasting effects on cortical excitability that persisted beyond the actual stimulus delivery (Chen et al., 1997; Maeda, Keenan, Tormos, Topka, & Pascual-Leone, 2000). Given the ability of this treatment to modulate cortical activity in a focal way, focus was soon placed on the use of this technique to potentially ameliorate neuropsychiatric disorders, with the earliest studies attempting to treat depression (George et al., 1995; Hoflich, Kasper, Hufnagel, Ruhrmann, & Moller, 1993; Kolbinger, Hoflich, Hufnagel, & et al., 1995; Pascual-Leone, Rubio, Pallardo, & Catala, 1996). Since these first studies, numerous clinical trials of rTMS for the treatment of depression (and other psychiatric disorders) have been conducted.
In October 2008, an rTMS device was approved for use by the US Food and Drug Administration (FDA) for patients with major depression who have not responded to at least one antidepressant medication in their present episode. The approval for rTMS was not straightforward. Although a sham controlled trial demonstrated the superiority of active versus sham rTMS in the treatment of depression, the FDA did not initially support of the use of rTMS in treatment-resistant depression based on the submitted clinical data. Instead, the approval for rTMS was based on an FDA ruling that the rTMS device was sufficiently similar to existing devices that did not require a premarket approval application and allowed the device to be marketed in accordance with Section 510(k) of the federal Food, Drug, and Cosmetic Act for “the treatment of Major Depressive Disorder in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant medication at or above the minimal effective dose and duration in the current episode.” In 2013, Brainsway obtained Food and Drug Administration (FDA) approval for an rTMS device. Other companies are currently developing and testing rTMS devices for treatment-resistant depression and various other clinical disorders.
Depression is a complex neuropsychiatric syndrome consisting of abnormalities of mood, interest, sleep, appetite, energy, psychomotor activity, and cognition. Depressed patients often have excessive guilt and thoughts of death. In the most extreme cases, depressed patients may have psychosis, extreme anxiety, and/or suicidal ideation. Depression is associated with significant costs, including increased years lost due to disability (WHO, 2008), increased burden of disease (WHO, 2008), and increased mortality (Gallo et al., 2013). Standard treatments for depression include antidepressant medications and psychotherapy. In patients with severe and/or treatment-resistant depression, electroconvulsive therapy (ECT) may be used. ECT represents one of the oldest treatments for depression and remains one of the most effective. Up to 33% of patients may remit with first-line treatment for depression, and about two-thirds will remit with subsequent treatments (Holtzheimer & Mayberg, 2011; Rush et al., 2006). Up to 80% to 90% of depressed patients may remit with ECT (Prudic et al., 1996), though response is lower in patients with prior treatment resistance (Kellner et al., 2006; Sackeim et al., 2001). A common problem in the treatment of depression is preventing relapse. Even with treatment to remission, many patients with depression may relapse over the next 6 to 12 months; prior treatment resistance increases the rate of and decreases the time to relapse (Kellner et al., 2006; Rush et al., 2006; Sackeim et al., 2001). New treatments for depression are clearly needed.
Since the late 1800s, severe depression has been hypothesized to result from dysfunction within a network of brain regions involved in regulation of mood, thought, and behavior (Holtzheimer & Mayberg, 2011; Papez, 1937). With the advent of more advanced structural and functional neuroimaging over the past several decades, the specifics of this network have become better understood (Drevets, Price, & Furey, 2008; Mayberg, 2009). Some of the most commonly implicated brain regions include the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex, orbitofrontal cortex, cingulate gyrus (including dorsal anterior, perigenual, subgenual, and posterior subdivisions), insular cortex, medial temporal lobe regions (hippocampus, parahippocampus, and amygdala), parietal cortex, thalamus, midbrain structures (including dorsal and ventral striatum, hypothalamus), and brain stem regions. Abnormalities in these various regions have been identified in depressed patients versus healthy controls. Further, changes in specific brain regions have been associated with antidepressant effects of various treatments. One of the most common findings comparing depressed patients to controls is abnormal activity (typically reduced) of the dorsolateral prefrontal cortex (DLPFC) (Baxter et al., 1985; Bench et al., 1992; Videbech, 2000). This finding helped support some of the earliest studies of rTMS for depression (George & Wassermann, 1994), with the hypothesis that rTMS might be able to reverse this abnormal DLPFC activity directly. In addition to targeting the neurobiology of depression very specifically, TMS offered potential advantages of not requiring anesthesia during treatment administration and the possibility of fewer cognitive side effects.
As the field has progressed, it has become clear that the effects of DLPFC rTMS are more complicated and likely involve “downstream” effects on other brain regions in the mood-regulation circuit. Specifically, DLPFC rTMS may serve to directly stimulate a critical node within a mood regulation network resulting in changes throughout this network that are effectively antidepressant. Within a proposed mood regulation network, the DLPFC is connected to a number of other regions. Several imaging studies have shown that the effects of focal DLPFC TMS are likely widespread throughout this mood disorders network, associated with functional changes in remote brain activity (Kimbrell et al., 1999, 2002; Paillere Martinot et al., 2011; Paus & Barrett, 2004; Speer et al., 2003; Strafella, Paus, Barrett, & Dagher, 2001). Therefore, though rTMS is a “focal” neurostimulation technique, its mechanism likely involves modulation of activity throughout a network of brain regions involved in mood regulation, depression, and the antidepressant response.
This handbook is for clinicians who use rTMS as an intervention for patients with depression. George and Taylor discuss the theoretical basis of TMS, describing the neurophysiologic effects of this intervention and the rationale for currently used treatment parameters. Epstein then describes the development of TMS technology, emphasizing advances in coil design that have led to clinically useful TMS systems. Moyer et al. present the clinical data supporting the use of rTMS as a treatment for depression. These include data from pivotal clinical trials as well as preliminary data from “real-world” clinical settings. Next, Rossi and Lefaucheur discuss the safety of rTMS and discuss common adverse events. Rosenquist and McCall then present issues related to the selection and management of patients with depression presenting for rTMS treatment. Maixner elaborates on practical elements involved in developing a clinical rTMS service. McClintock and Potter discuss the use of various measures to enhance the efficacy of rTMS delivery in the clinical setting. Radhu et al. then describe the current and anticipated use of neurophysiologic measures to optimize the use of rTMS for the treatment of depression. Fitzgerald presents data on the use of rTMS more broadly, including novel parameter settings and the use of rTMS in conditions other than depression. Loo et al then discuss the clinical role of neurostimulation techniques beyond rTMS. Finally, Lisanby delineates the current limitations of TMS as a treatment for psychiatric disorders and highlights a number of promising directions for future research.
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