A Clinical Guide To Transcranial Magnetic Stimulation

A Clinical Guide to Transcranial
Magnetic Stimulation
A Clinical Guide to
Transcranial Magnetic
Stimulation
EDITED BY
Paul E. Holtzheimer, MD
Geisel School of Medicine at Dartmouth
Lebanon, NH
William M. McDonald, MD
Emory University School of Medicine
Atlanta, GA
3
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A Clinical Guide to Transcranial Magnetic Stimulation / edited by Paul E. Holtzheimer, William M. McDonald.
p. ; cm.
Includes bibliographical references.
ISBN 978–0–19–992648–0 (alk. paper)
I. Holtzheimer, Paul E., editor of compilation. II. McDonald, William M., 1953–editor of compilation.
[DNLM: 1. Mental Disorders—therapy. 2. Transcranial Magnetic Stimulation—methods. WM 400]
RC480.53
616.8906—dc23
2013034522
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Contents
Contributors vii
Introduction ix
Paul E. Holtzheimer and William M. McDonald
1 Theoretical Basis for Transcranial Magnetic Stimulation 1

Mark S. George and Joseph J. Taylor
2 Development of Transcranial Magnetic Stimulation Technology 8
Charles M. Epstein
3 Clinical Efficacy of Transcranial Magnetic Stimulation in Depression 17
Michelle L. Moyer, Mario A. Cristancho and John P. O’Reardon
4 Safety of Transcranial Magnetic Stimulation 32
Simone Rossi and Jean-Pascal Lefaucheur
5 Patient Selection and Management 52
Peter B. Rosenquist and W. Vaughn McCall
6 Practical Administration of Transcranial Magnetic Stimulation
in a Clinical Setting 69
Daniel F. Maixner
7 Measurement-Based Care in Transcranial Magnetic Stimulation Practice 82
Shawn M. McClintock and Guy Potter
8 Neurophysiological Measurements Associated with Transcranial
Magnetic Stimulation 98
Natasha Radhu, Daniel M. Blumberger, Anosha Zanjani,
and Zafiris J. Daskalakis
9 Transcranial Magnetic Stimulation in the Treatment of Psychiatric
and Neurological Disorders 117
Paul Fitzgerald
vi | C o n t e n t s
10 Development of Other Neurostimulation Interventions 136

Colleen Loo, Scott Aaronson, and Paul E. Holtzheimer
11 Limitations of Transcranial Magnetic Stimulation and Future Directions
for Clinical Research 152
Sarah H. Lisanby
Index171
Contributors
Scott Aaronson, MD Paul Fitzgerald, MD, PhD

Sheppard and Enoch Pratt Hospital Monash Alfred Psychiatry Research Centre
Towson, Maryland Melbourne, Australia
Daniel M. Blumberger, MD Mark S. George, MD

Temerty Centre for Therapeutic Brain Stimulation Laboratory
Intervention SC Brain Imaging Center of Excellence
Centre for Addiction and Mental Health Medical University of South Carolina
University of Toronto Charleston, South Carolina
Toronto, Ontario, Canada
Paul E. Holtzheimer, MD
Mario A. Cristancho, MD Director, Mood Disorders Service, Geisel
Neuromodulation Program, Department of School of Medicine at Dartmouth
Psychiatry Lebanon, NH
University of Pennsylvania
Philadelphia, Pennsylvania Jean-Pascal Lefaucheur, MD, PhD
Hôpital Henri Mondor
Zafiris J. Daskalakis, MD, PhD Department of Physiology
Temerty Centre for Therapeutic Brain University of Paris
Intervention Paris, France
Centre for Addiction and Mental Health
University of Toronto Sarah H. Lisanby, MD
Toronto, Ontario, Canada Department of Psychiatry & Behavioral
Sciences
Charles M. Epstein, MD Duke University School of Medicine
Department of Neurology Durham, North Carolia
Emory University School of Medicine
Atlanta, Georgia
viii | C o n t r i b u t o r s
Colleen Loo, MD Guy Potter, PhD

School of Psychiatry Department of Psychiatry and Behavioral
University of New South Wales Sciences
Sydney, Australia Duke University School of Medicine
Durham, North Carolina
Daniel F. Maixner, MD
Department of Psychiatry Simone Rossi, MD, PhD
University of Michigan Azienda Ospedaliera-Universitaria Senese
Ann Arbor, Michigan Brain Investigation &
Neuromodulation Lab
W. Vaughn McCall, MD, MS Policlinico Le Scotte
Department of Psychiatry and Health Sienna, Italy
Behavior
Medical College of Georgia–Georgia Peter B. Rosenquist, MD
Regents University Department of Psychiatry and Health
Augusta, Georgia Behavior
Medical College of Georgia–Georgia
Shawn M. McClintock, PhD Regents University
Psychiatry and Behavioral Sciences Augusta, Georgia
Duke University School of
Medicine Natasha Radhu
Durham, North Carolina Temerty Centre for Therapeutic Brain
Intervention
William M. McDonald, MD Centre for Addiction and Mental Health
J.B. Fuqua Chair for Late-Life Depression University of Toronto
Department of Psychiatry and Behavioral Toronto, Ontario, Canada
Sciences
Emory University School of Medicine Joseph J. Taylor, MD, PhD
Brain Stimulation Laboratory
Michelle L. Moyer, MD SC Brain Imaging Center of Excellence
Neuromodulation Program Medical University of South Carolina
Department of Psychiatry Charleston, South Carolina
Rowan University School of Osteopathic
Medicine Anosha Zanjani
Stratford, New Jersey Temerty Centre for Therapeutic Brain
Intervention
John P. O’Reardon, MD Centre for Addiction and Mental Health
Neuromodulation Program University of Toronto
Department of Psychiatry Toronto, Ontario, Canada
Rowan University School of Osteopathic
Medicine
Stratford, New Jersey
Introduction
Paul E. Holtzheimer and William M. McDonald
Transcranial Magnetic Stimulation

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 corti-
cal 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.
Current Status of TMS for Depression

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
x | I n t r o d u c t i o n
a sham controlled trial demonstrated the superiority of active versus sham rTMS in the treat-
ment 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.
Rationale for TMS for Depression

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 pre-
venting 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 treat-
ments for depression are clearly needed.
Since the late 1800s, severe depression has been hypothesized to result from dysfunc-
tion 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 struc-
tural and functional neuroimaging over the past several decades, the specifics of this net-
work 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 tempo-
ral 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
I n t r o d u c t i o n | xi
versus healthy controls. Further, changes in specific brain regions have been associated with
antidepressant effects of various treatments. One of the most common findings compar-
ing depressed patients to controls is abnormal activity (typically reduced) of the dorsolat-
eral 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 abnor-
mal 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, asso-
ciated 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 mecha-
nism likely involves modulation of activity throughout a network of brain regions involved
in mood regulation, depression, and the antidepressant response.
Overview of this Handbook

This handbook is for clinicians who use rTMS as an intervention for patients with depres-
sion. George and Taylor discuss the theoretical basis of TMS, describing the neurophysio-
logic 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 neurostimula-
tion 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.
xii | I n t r o d u c t i o n
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1
Theoretical Basis for

Stimulation
Mark S. George and Joseph J. Taylor
Overview: From Spirits to Stimulation

The mechanisms underlying human behavior have intrigued physicians, scientists, and phi-
losophers 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 sci-
entific 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 magne-
tism. 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
2 | A C l i n i ca l G u i d e to T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n
brain stimulation leading into the 19th century. Capitalizing on a serendipitous observa-
tion 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 impor-
tant 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 envi-
ronment 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 mon-
keys 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 neurophysi-
ological 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.
Discovery of the Important Concepts Behind

Transcranial Magnetic Stimulation
Brief History
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 stu-
dents 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
T h e o r e t i ca l B a s i s for T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n | 3
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 prefron-
tal 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 Basics
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).
TMS and Neuroplasticity

One of the basic tenets of rTMS therapy is that its behavioral effects persist after the stimula-
tion 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 excit-
ability, low-frequency stimulation (e.g., 5 Hz) decreases cortical excitability. The mecha-
nisms 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 physiologi-
cal 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 neu-
rophysiological 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.
Summary
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 neu-
rophysiology as well as for mapping and modulating neural circuitry.
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2
Development of Transcranial
Technology
Charles M. Epstein
The fundamental concepts behind transcranial magnetic stimulation (TMS) are more than a
century old. James Clerk Maxwell’s laws of electromagnetism were codified in the 1860s, and
the electrical nature of brain activity was understood by the following decade (Caton, 1875).
For many years, however, attempts at noninvasive electromagnetic brain stimulation were
frustrated by the need to switch enormous currents on and off at speeds measured in micro-
seconds. The first successful device was built by Anthony Barker at the University of Sheffield
in the 1980s (Barker, Jalinous, and Freeston, 1985) and came to be designated as “magnetic”
stimulation to distinguish it from older methods involving direct electrical contact, such as
electronconvulsive therapy.
The stimulation coil on the head is, in many ways, the central element of the entire
TMS system. As the part in closest contact with the subject, its design and construction are
fundamental to patient safety. The coil determines the distribution of induced electric cur-
rents within the brain, is a core component of the basic excitation circuit, and is the most
important determinant of overall stimulator efficiency.
Core TMS Circuit

Many magnetic stimulators are based on circuit 1, shown in Figure 2.1A, and include the
following components: a source of high-voltage electric current, a capacitor that receives the
current and stores energy in the form of electric charge, an induction coil through which that
charge will flow to produce a magnetic field, and an electronic switch that allows current to
rapidly surge from one to the other.
The combination of capacitor and coil is known to engineers as a resonant circuit and
can be thought of as the electrical equivalent of a pendulum (Figure 2.1B). The electric charge
Development of T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n T e c h n o l o g y | 9
stored in the capacitor represents potential energy, just as a pendulum lifted to one side holds
the potential energy of the gravitational pull on the weight. When the pendulum is released
and swings into a vertical position, all of its potential energy has been transformed into the
kinetic energy of the moving weight. As the pendulum swings fully to the other side, the kinetic
energy is again converted to potential energy. The idea of kinetic energy in a moving weight is
simple and intuitive, whereas the concept of kinetic energy in electric current passing through
a coil of wire is less obvious. However, closing the switch in Figure 2.1A does the same thing as
releasing the pendulum in Figure 2.1B, that is, the current will flow back and forth indefinitely
between the capacitor and the coil until dissipated by friction (which for electricity is termed
“resistance”). Both the resonant circuit and the pendulum oscillate at specific frequencies deter-
mined by their components. Unlike a pendulum, however, the current in magnetic stimulators
is allowed to swing through only a single cycle before the oscillation is terminated. (Instantly
stopping thousands of amperes is the tricky part of this particular design, but will not be dis-
cussed here.) The result of one full current cycle is one TMS pulse, with the added benefit that
most of the current ends up back in the capacitor rather than being lost as heat.
Circuit 2 in Figure 2.2 was more commonly used in the early development of TMS. It
looks more complicated than circuit 1 but is easier and cheaper to build. It includes a diode,
which diverts current coming out of the coil when the current direction begins to reverse; this
is the equivalent of a pendulum beginning to swing in the other direction. The entire current is
then dissipated into a large resistor, which has the same effect as putting a brake on the pendulum.
(A) Switch
+ +++ +++
– ––– –––
Voltage Capacitor Inductor

Source
(B)
Potential
Energy
Kinetic Energy
F I GUR E 2.1 (A)

Circuit 1 is the most basic type of TMS circuit. It includes a voltage source, a capacitor,
a switch to release the current, and an induction coil. (B) A simple pendulum, which is analogous to
the basic TMS circuit. When the pendulum is raised to one side, it stores potential energy, similar to a
charged capacitor. Once the pendulum is released and reaches bottom, all of the energy is kinetic, just
as all the energy of the TMS circuit is in the coil when the current is maximum. The pendulum and the
TMS circuit can swing back and forth repeatedly between states of stored and kinetic energy.
Switch
+ +++ +++ Diode
– ––– –––
Resistor
Voltage Capacitor Inductor

Source
F I GUR E 2.2 Circuit
2 is another type of TMS circuit in which the current is shunted into a resistor half-
way through a single oscillation, similar to braking a pendulum after just half a cycle.
This type of circuit is quite wasteful of electricity. The energy cost is tolerable for single pulses
or with brief trains of slow, repetitive stimulation. However, for fast, repetitive stimulation, the
power requirements and large amounts of heat produced by circuit 2 can easily become unac-
ceptable. Other, more complex but more adjustable driving circuits have been devised; however,
these circuits have not been widely adopted (Peterchev, Jalinous, and Lisanby, 2008).
The electric current moving through the coil generates a magnetic field, making that coil
an electromagnet. Like the permanent magnets stuck to a refrigerator, an electromagnet can
attract iron objects nearby. However, it will not necessarily produce TMS. Only a changing
magnetic field can induce electric current in nearby electrical conductors, for example, the
brain, and thereby depolarize neurons. To stimulate neurons with a varying magnetic field,
the voltage, current, and rate at which they change must all attain impressively large values.
Typically, the capacitor is charged to a few thousand volts, the peak current through the coil
reaches several thousand amperes, and the current oscillates through an entire cycle in well
under 1/1000 of a second. For comparison, in North America an old-fashioned 100-watt
incandescent light bulb runs on 120 volts and less than 1 ampere. During the tiny fraction of a
second in which TMS coil current is flowing, typical systems are operating at millions of watts.
The peak magnetic field is in the range of 1 Tesla, around 20,000 times the Earth’s magnetic
field. All that energy, and the heat it produces, must be safely isolated from the subject’s head!
Coil Configuration
All TMS coils have the following fundamental design constraints: they must lie directly
against the subject’s head, heavy wires must be used to carry the large currents involved, the
wires are subject to substantial magnetic forces during every pulse, and the heat those pulses
generate must be dissipated while insulating the wires from the patient and operator. Since
TMS was first introduced, researchers and engineers have proposed a striking variety of coil
configurations, all intended to optimally focus the induced electric current within the brain
(Hsu and Durand, 2001; Kraus, Gugino, Levy, Cadwell, and Roth, 1993; Lontis, Voigt, and
Struijk, 2006; Ren, Tarjan, and Popovic, 1995; Roth, Zangen, and Hallett, 2002; Ruohonen,
Virtanen, and Ilmoniemi, 1997). Recently Deng and colleagues (2013) reported that the
final output of these varied designs could be reduced to two fundamental arrangements: a
round coil and a double (figure-8) coil. These are illustrated in Figure 2.3.
F I GUR E 2 .3
Round and figure-8–shaped TMS coils. The area in orange indicates the approximate areas
covered by the induced electric fields. The partial red circle and red arrows indicate the direction of the
electric currents within the brain.
The essential feature of a single circular coil is that the brain currents it induces are
maximal beneath its outer edge, not beneath the center. This behavior is not intuitive, espe-
cially since the peak magnetic field occurs at the coil center. Placing the center of the coil over
the presumed target in the brain is likely to produce puzzling results, not to mention disap-
pointment in terms of research results and treatment outcomes. Round coils do have advan-
tages, including simple construction, straightforward heat dissipation, stable head contact,
and relatively good penetration beneath the scalp surface. However, the near impossibility of
aiming the coils toward a single brain region limits their utility in most applications.
The double coil consists of two round coils placed side by side to form a shape variously
described as a figure-8 or a double D. A double “cone” coil is a figure-8 bent to an acute angle
at less than 180 degrees, which somewhat improves efficiency and penetration (Lontis, Voigt,
and Struijk, 2006). The currents in the two coils run parallel at their junction, reinforcing
each other to produce the maximum magnetic field and maximum brain current beneath
the center where they form an elongated oval running parallel to the coil junction. Thus, coil
placement is greatly simplified and the area of stimulation is more compact. For all types of
coils, the induced brain currents run parallel to the current in the overlying coil wires but in
the opposite direction. Those currents are invariably parallel to the brain surface, another
constraint produced by the physics of current flow within a volume conductor. Tilting the
coil on the head will alter the distribution of induced brain currents but not its orientation.
The majority of TMS testing and treatment involves positioning the maximum
induced current (lying beneath the center of a figure-8 coil) at a specific cortical target. For
depression treatment and many other applications, a common target is the left dorsolateral
prefrontal cortex (DLPFC). This position may be located by methods as simple as measur-
ing from specific skull landmarks (fiducials) or as sophisticated as infrared neuronavigation,
with a model of the induced electric field projected into an image of the patient’s anatomical
magnetic resonance image (MRI). Unfortunately, for many applications outside the motor
cortex, our knowledge of the exact functional target area in the brain is less precise than our
ability to position the coil over individual gyri. Fox and colleagues (2012) proposed target-
ing depression treatment to specific subregions of the DLPFC, determined through correla-
tion of resting-state functional MRI activity with the subgenual cingulate region and other
areas. If successful, such techniques could rationalize coil positioning and improve treatment
response.
Larger coils stimulate wider and deeper volumes of the underlying brain. This may be
a disadvantage if the target can be precisely localized. If the area of stimulation is larger than
the intended target, the overlap might be useful in ensuring that the stimulus hits the target
despite localization errors, or it might be counterproductive by producing effects that are dif-
ferent or even contrary to those intended. Synchronous stimulation that extends over larger
regions of cortex might possibly increase the risk of seizure as well. Because the vast majority
of TMS studies to date have used only a single coil type and size, the data needed to clarify
these issues are largely lacking.
The most ambitious goal of TMS coil design has been to focus stimulation on regions
deep beneath the superficial cortex. Success at this objective has been quite limited and is
likely to remain so. The extensive analysis by Deng and colleagues (2013) indicates that the
physics of induced electric currents outweighs magnetic coil geometry and that large altera-
tions in coil shape tend to produce smaller effects on the actual depth of stimulation. Even
theoretically, it appears impossible to induce currents that are stronger at depth than at the
brain surface (Heller and van Hulsteyn, 1992). To the extent that somewhat deeper brain
penetration is possible, it requires larger coils, and larger coils, in turn, mandate larger vol-
umes of brain stimulation. It is not possible to dissociate these two variables. Any claim that
a special arrangement of TMS coils can focus stimulation to a small region beneath the brain
surface should be assessed with serious skepticism.
As the intensity, frequency, and duration of TMS increase, the difficulty in deliver-
ing all that coil current and in removing all the heat it generates increases correspondingly.
Doubling the induced current within the brain requires four times the power and generates
four times as much heat. Thus, systems designed for treatment using rapid, repetitive TMS
tend to be physically large, pull large amounts of power from the electrical mains, and require
cooling by air, water, or oil to prevent the coil from overheating during use. Air-cooling
appears to be the safest of these methods. To avoid the need for special cooling while sub-
stantially improving stimulation efficiency, a figure-8–type coil can be modified with an iron
core constructed from specialized magnetic materials (Epstein and Davey, 2002).
Safety and Other Coil Considerations

The surface temperature of TMS coils and other objects that contact patients is strictly regu-
lated by engineering codes. In the United States, the upper limit is 41ºC. Commercial coils
are generally equipped with internal sensors and automatically shut down when this limit is
exceeded. At all points, the coil, lead wire, and connectors must be insulated to several times
the maximum stimulator voltage.
The magnetic field within the coil generates a mechanical force on the windings that
is responsible for the audible click that accompanies every pulse. The coil enclosure must
protect against cracking and even fragmentation over prolonged use that includes repeated
cycles of heating and cooling. At times, TMS users have attempted to cool their coils by
submerging them in ice water—a measure that is liable to accelerate material fatigue and
is absolutely contraindicated during clinical use. Internal mechanical forces rise as the coil
dimensions are reduced. This is one of several considerations that make very small coils
impractical.
Estimating the Intensity and Effects of TMS

The earliest and most obvious effect of TMS was twitching of the limbs when the coil was
placed over motor cortex (Barker, Jalinous, and Freeston, 1985). The easiest muscles to acti-
vate are those in the hand and distal upper limb due, in part, to the convenient location of
the hand motor area in the central convexity of the brain and, in part, to physiology; these
muscles have the purest component of corticospinal innervation from the opposite hemi-
sphere. It is surprising, and still unexplained, that TMS can activate many more muscles,
more reliably, than can direct electrical stimulation of the cerebral cortex during brain map-
ping in patients who are awake.
The extent of TMS muscle activation can be recorded with surface electrodes placed
over muscles of interest, using the same basic recording technology as used in peripheral
nerve conduction studies. The simplest and most easily quantified measure of muscle con-
traction is motor threshold, that is, the intensity of stimulation that produces the smallest
reproducible activation of the tested muscle. A vast number of factors have been shown to
influence motor threshold, including genetics, handedness, hormonal variation, sleep depri-
vation, drugs, neurological disease, prior contraction of the tested muscle, and even think-
ing about moving the tested muscle. Reduced motor threshold is considered to represent a
state of greater cortical excitability, and higher threshold a state of lower excitability. Some
of the factors that change motor threshold have intuitive face validity. For example, mental
preparation for movement and drugs with proconvulsant effects lower it (Mars, Bestmann,
Rothwell, and Haggard, 2007; Mufti et al., 2010), while many drugs used to treat seizures
elevate it (Lee, Seob, Cohen, Bagica, and Theodore, 2005; Ziemann, Steinhoff, Tergau, and
Paulus, 1998).
Since any baseline muscle contraction must be quantified (and thereby adds another
variable), motor threshold is most often estimated in a relaxed state and referred to as the
resting motor threshold (RMT). RMT is the most frequent measure applied in the universe
of TMS, with a usual target of 50 or 100 microvolts peak-to-peak. Even when it is not actu-
ally the measure of interest, RMT is widely used to establish a baseline of brain excitability
for individual subjects and thereby to adjust the intensity of stimulation for other measure-
ments or for treatment. Although RMT has turned out to be an imperfect predictor of the
threshold to TMS effects in nonmotor regions, its extensive use testifies to the conviction
that an imperfect estimate of brain excitability is superior to no predictor at all. In particu-
lar, some type of excitability measure is essential for comparing the brain effects produced
by many different stimulators, pulse parameters, and coils, primarily for establishing TMS
safety limits in order to avoid induction of seizures and other potential adverse events. RMT
has been estimated by visual and neurophysiological criteria and quantified by different sta-
tistical techniques (Mishory et al., 2004; Rossini et al., 1994). Present evidence suggests that
neurophysiological measures may be more reliable than visual ones (Anderson and George,
2009) and that a simple parameter estimation technique is likely to represent the best combi-
nation of accuracy and efficiency (Borckardt, Nahas, Koola, and George, 2006).
The most widely cited TMS safety data, which were compiled at the US National
Institutes of Health (NIH), are given in Table 2.1 (Wassermann, 1998). Additional findings
suggest that the intervals between trains of pulses should be 5 seconds or more (Chen et al.,
1997). These safety limits have received extensive comment and modification and have become
fundamental to the design of TMS research and treatment protocols (Rossi, Hallett, Rossini,
and Pascual-Leone, 2009). Exceeding these limits should not be contemplated except under
exceptional circumstances. At the same time, remaining within those limits should never be
misunderstood as a guarantee of absolute safety. The existing guidelines should, at best, be
considered provisional. However, the progressive tightening of regulations related to research
on human volunteers means that more comprehensive studies might never be performed.
The fundamental limitations of the NIH safety study include its small number of sub-
jects, all without significant neuropsychiatric deficits, neither very young nor very old, and
relatively unstressed. The investigators applied a set of stimulation parameters and coils that
were in use at the time. No additional safety data are available regarding the total number of
trains and stimuli delivered in a single session or a single day, although many thousands of
pulses have been used in 1 day without apparent adverse events (Holtzheimer et al., 2010).
It is not possible to extrapolate from the available data to statistical confidence limits for the
general population, much less for the extended range of TMS systems and parameters that
have been introduced since the original studies. In addition, it has become clear that many
individual factors such as genetic susceptibility, sleep deprivation, use of or withdrawal from
various medications, and presence of major psychiatric disorders can contribute substantially
to seizure risk (Alper, Schwartz, Kolts, and Khan, 2007; Hesdorffer, Hauser, Annegers, and
Cascino, 2000; Huber et al., 2013; Kreuzer et al., 2011). New drugs are constantly being
introduced. Newer TMS pulse sequences such as “theta burst” cannot be directly compared
with older ones. TMS coils intended to produce deep penetration can achieve this only by
TABLE 2.1 Maximum Safe Train Duration as a Function of Intensity

and Frequency
Frequency (Hz) TMS Intensity as % of Motor Threshold
90% 100% 110% 120% 130%
1 >1800 >1800 >1800 > 360 >50

5 >10 >10 >10 >10 >10
10 >5 >5 >5 4.2 2.9
20 2.05 2.05 1.6 1.0 0.55
25 1.28 1.28 0.84 0.4 0.24
Duration is in seconds. Frequency (Hz) of TMS intensity presented as a percent of motor threshold.
Data from Wassermann et al., 2008.
delivering even stronger stimulation to large volumes of superficial cortex; doing so may alter
safety boundaries in ways that are difficult to predict. As a result of all these uncertainties, cen-
ters that perform TMS treatment should assume that even with “safe” settings, rare seizures
are going to occur, and these centers should be prepared to deal with them appropriately.
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3
Clinical Efficacy of Transcranial

Magnetic Stimulation in
Depression
Michelle L. Moyer, Mario A. Cristancho,
and John P. O’Reardon
Introduction
First emerging as a potential tool for noninvasive neuronal stimulation in the early
20th century (Thompson, 1910), repetitive transcranial magnetic stimulation (rTMS)
has undergone multiple stages of development. Anthony Barker invented the first
modern-day rTMS device in 1985 as a way to study electrophysiology (Barker, Freeston,
Jalinous, Merton, and Morton, 1985). In 1995, George et al. (1995) used rTMS to target
specific prefrontal brain regions thought to be involved in the etiology or pathophysi-
ology of major depression in an open-label study. Since then, the rTMS literature has
accumulated more than 15 years of research and at least 30 published randomized con-
trolled trials (RCTs). Although most of the research has supported the antidepressant
properties of rTMS, the degree of clinical benefit has been variable and, in some cases,
marginal. However, a clear trend toward more robust effects has been seen as both stimu-
lation technique (e.g., dose, coil placement, and course duration) and research quality
(e.g., better sham stimulation and larger sample sizes) improve. rTMS has become a rec-
ognized, accepted, and clinically available therapeutic intervention. The US Food and
Drug Administration (FDA) cleared TMS for the treatment of adults with nonpsychotic
major depression in October 2008.
In this chapter we review the efficacy of left dorsolateral TMS as a treatment for major
depression, focusing on the large-scale RCTs underpinning its efficacy. We also review the
broader synthesis of efficacy data in the metaanalyses that have been conducted and reported
in the literature. Now that TMS is available in clinical practice in the United States, effec-
tiveness data have emerged, and it is reviewed here. Last, emerging data on efficacy in special
populations (e.g., adolescent depression and depression during pregnancy) is examined.
Results from Large-Scale RCTs

There have been three large-scale studies (sample size >100) of rTMS in major depres-
sion: one industry-sponsored study that led to FDA approval, a National Institutes of Health
(NIH)–funded study with dosage parameters similar to those in the industry-sponsored
study but with design enhancements, and a European study of the augmentation effects of
rTMS when used in combination with pharmacotherapy (Herwig et al., 2007; O’Reardon
et al., 2007; George et al., 2010).
In the industry-sponsored,1 multicenter (23 sites) RCT, 301 medication-free patients
with treatment-resistant depression (TRD) were randomized to either active rTMS or sham
stimulation (O’Reardon et al., 2007). The trial was intended to provide the necessary data
for premarket approval by the FDA and required that the company show the efficacy and
safety of the device in a sham-controlled trial. Total score change in the Montgomery–
Asberg depression rating scale (MADRS) after 4 weeks of treatment was used as the primary
outcome measure. Secondary outcomes included MADRS score at week 6 and Hamilton
depression scale (HAMD) 17- and 24-item scores at weeks 4 and 6. For the primary outcome
measure, active rTMS was superior to sham stimulation (P = 0.038), but only following cor-
rection for a baseline difference in MADRS scores between the two groups.
Active stimulation was also statistically superior to sham based on categorical out-
comes with response rates (≥50% reduction from baseline) almost two-fold higher on all
three scales at week 4 (MADRS, 18.1% active versus 11.0% sham; HAMD-17, 20.5% active
versus 11.6% sham; and HAMD-24, 19.4% active versus 11.6% sham). This difference in
response rates was sustained and statistically significant at week 6. Remission (MADRS <10,
HAMD-24 <11, and HAMD-17 <8) rates were approximately three-fold higher with active
stimulation at week 6 (14.2% active versus 5.5% [P < 0.05] by MADRS; Figure 3.1). Of
note, the study sample was moderately treatment resistant, with up to four failed adequate
antidepressant trials in the current episode (mean = 1.6 failed antidepressant trials). In addi-
tion, the stimulation dose was 3000 pulses per day (high frequency over the left dorsolateral
prefrontal cortex [DLPFC] that, although less than the number of pulses used in off-label
clinical practice (up to 8000 pulses per day), was higher than the doses used in previous stud-
ies (O’Reardon et al., 2007).
Although the categorical results in terms of response and remission rates were reassur-
ing, albeit somewhat low, the failure to show a statistically superior response of active versus
sham treatment on the a priori primary measure (continuous change on the MADRS scale)
created some disagreement among those on the FDA advisory panel who evaluated the effec-
tiveness of rTMS for the treatment of depression. In 2007, the FDA advisory panel did not
approve rTMS for the treatment of depression, stating that the device was safe but that the
efficacy was based on a post hoc analysis and therefore subject to potential bias (Scudiero,
2007). However, in October 2008, the FDA reevaluated Neuronetics’ application for the
rTMS device under Section 510(k) of the Federal Food, Drug, and Cosmetic Act. This pro-
vision allows approval of a device if the device is sufficiently similar to existing devices and
1. The trial was sponsored by Neuronetics, which was seeking FDA approval for their rTMS device.
C l i n i ca l E f f i cac y of T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n in D e p r e s s i o n | 19
Response Rates (%) Remission Rates (%)
Active - Response Rate Active - Remission Rate

Sham - Response Rate Sham - Remission Rate
23.9**
14.2*
18.1*
12.3 7.1
11
6.2
8.4 5.5
6.2 3.9
2.1
Week 2 Week 4 Week 6 Week 2 Week 4 Week 6
F I GUR E 3 .1 Acute
response and remission rates from the pivotal trial that resulted in FDA approval.
*P < .05 versus sham; **P < .01 versus sham, LOCF analysis. LOCF = Last Observation Carried Forward.
requires that the company demonstrate that the device is safe but does not require that the
company demonstrate superiority to sham in an RCT. The Neuronetics Neurostar rTMS
device was approved under Section 510(K) (Melkerson, 2008) 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 dura-
tion in the current episode.”
The FDA approval specifically cited the use of rTMS in patients who had failed
to achieve satisfactory improvement from one prior adequate antidepressant medication
in the current episode. This approval was based on the post hoc analysis of patients in
the pivotal trial who failed only one prior antidepressant trial (n = 164) that resulted
in a clear superiority of active rTMS versus sham as early as week 2, with response rates
by MADRS of 10.2% versus 4.0%, at week 4 of 20.5% versus 9.2%, and at week 6 of
25.0% versus 9.2% (Lisanby et al., 2009). This narrow label provides guidance for cli-
nicians about patients who are most likely to respond to rTMS. However, in a practi-
cal sense, few patients present as possible rTMS candidates at that relatively low level of
treatment resistance. Off-label rTMS is frequently used in patients with more TRD, a
practice that is supported by the effectiveness data from clinical practice that has recently
been published (Carpenter et al., 2012; Connolly, Helmer, Cristancho, Cristancho, and
O’Reardon, 2012).
Open-Label Extension Phase of the

Industry-Sponsored Trial
Patients whose HAMD-17 score did not decrease by more than 25% of their baseline score
after 4 weeks of blinded treatment during the acute phase entered an open-label extension
phase (Avery et al., 2008). Of the 158 patients who enrolled in the open-label phase, 85 had
originally been assigned to the sham arm and 73 had originally been assigned to the active
arm (the extended rTMS group). The primary outcome measure for the extension phase
was the baseline-to-endpoint (i.e., 6 week) change in MADRS score. Those who had been
originally assigned to the active arm showed a response rate of 26% and a remission rate of
11%. Those who had originally been assigned to sham showed a response rate of 42.4% and a
remission rate of 20%. During the 3-week taper phase (six sessions of TMS over 3 weeks with
transition to antidepressant medication), remission rates by MADRS parameters increased
further to 17.6% for the extended TMS group and to 30.6% for the sham-to-rTMS group.
Numbers were slightly higher but comparable for the HAMD-24 scores (Avery et al., 2008).
These data support the concept that some patients may require extended rTMS sessions in
order to attain remission, although the data are limited by the open-label study design.
NIH’s Optimization of TMS Trial

A second large RCT (n = 190) sponsored by the NIH replicated the results from the
industry-sponsored trial after 3 weeks of treatment (George et al., 2010). In this study,
medication-free TRD patients (mean = 1.5 failed antidepressant trials) received either
active rTMS or sham stimulation. The study procedures were similar to those used in the
industry-sponsored trial with the differences being a better placebo control (i.e., improved
sham coil) and more accurate targeting with magnetic resonance imaging (MRI). The sham
coil was an active scalp stimulation, which ensured fully adequate blinding, and scalp location
could be adjusted anteriorly by 1 cm depending on MRI results to ensure accurate targeting
on the DLPFC. The primary outcome measure was remission rate, which was defined as
HAMD score ≤3 or two consecutive HAMD scores ≤10. Remission rate in patients receiv-
ing active stimulation was 14%, which was superior to those receiving sham stimulation (5%)
at week 3 (P = 0.02), and the number needed to treat (NNT)2 was 12 (George et al., 2010).
Of note, these remission rates are similar to the rates reported in the industry-sponsored trial
at week 6.
Open-Label Extension Phase of the NIH Trial

Those patients who did not improve significantly (defined as ≥30% reduction in HAMD
score) after 3 weeks of blind treatment in the optimization of TMS (OPT-TMS) trial
were given the option to enter an open-label phase trial (phase 2) and received 3 weeks
of high-frequency rTMS at 120% motor threshold (MT) over the left DLPFC for a
total of 3000 pulses per session. Those who did not respond after 3 weeks of open-label,
high-frequency rTMS (n = 81) received up to 4 weeks of slow-frequency rTMS at 120% MT
over the right DLPFC for 1800 pulses per session; 26% subsequently achieved remission. Of
all the patients in the OPT-TMS phase 2 trial (n = 141), 30.5% met criteria for remission,
while 41% met criteria for response; original treatment assignment (active versus sham in
phase 1) was not statistically associated with remission (McDonald et al., 2011).
2. The NNT is the number of patients who need to be treated to keep one patient from remaining depressed. For
example, if the NNT was 1, then every patient treated would have a positive antidepressant response. The higher
the NNT, the less effective the treatment; 2.3 is a relatively good NNT. As a comparator, the NNT for antidepres-
sant medication is 7–9 (Arroll et al., 2009).
Combination Trial
The third large-scale RCT was conducted in Europe (n = 127). This study did not exam-
ine rTMS as a stand-alone therapy but rather tested for an accelerating antidepressant effect
when a patient was randomized to simultaneously start on an antidepressant or placebo. The
investigators measured outcomes after 3 weeks of rTMS at 110% MT over the left DLPFC
for 2000 pulses per session. Response rates were not statistically different in the two treat-
ment groups. Thus, rTMS in combination with an antidepressant did not increase antide-
pressant response (Herwig et al., 2007).
Levels of Evidence
Despite the publication of results from relatively large sham-controlled trials, systematic
reviews of the extant literature are important to gain a more comprehensive picture of rTMS
efficacy. Metaanalyses that include good-quality and homogeneous RCTs are categorized at
level 1 evidence of efficacy according to the Oxford 2011 Levels of Evidence guidance (2012).
Briefly, levels of evidence range from 1 to 5, with 1 being the most scientifically reliable and
5 being the least scientifically reliable (e.g., expert opinion). Levels can be graded up or down
depending on variables such as the quality or consistency of the study in question. In general,
cohort studies are level 2, case-control studies are level 3, and case series are level 4 (Oxford
2011 Levels of Evidence, 2012).
Role of Metaanalyses
The major benefit of a metaanalysis is to synthesize the results of many smaller studies into
one large study, which then increases study power. In this case, “power” is defined as the
probability that the outcome or change in the dependent variable (i.e., improvement in
depression) is actually related to the intervention or independent variable (i.e., rTMS).
Therefore, higher power equals higher confidence in the effect of an intervention. In addi-
tion, metaanalyses gather the available evidence in a single study so that a clinician need not
look up every trial on a particular intervention before making a clinical decision. Still, this
methodology is not perfect and can suffer from significant issues of bias, both due to selec-
tion and statistical methods (Gavaghan, Moore, and McQuay, 2000; Chan, Hrobjartsson,
Haahr, Gotzsche, and Altman, 2004; Wood et al., 2008).
Metaanalyses of TMS Efficacy in Major

Depression
To date, at least 11 metaanalyses have been published, with most of them finding that rTMS
is statistically superior to sham for the treatment of major depression. Initial metaanalyses
were published in early 2000. McNamara et al. (2001) included five studies and reported a
NNT of 2.3. Holtzheimer et al. (2001) included 12 studies in their analysis and obtained an
effect size of 0.81. These results are in line with those from Burt et al. (2002) and Kozel and
George (2002) who reported effect sizes of 0.62 and 0.53, respectively.3
More recent and larger metaanalyses continue to support the role of rTMS as an
effective and safe tool in the treatment of major depression. Lam et al. (2008) focused on
TRD and analyzed 21 RCTs (n = 899) in terms of response (≥50% reduction in HAMD
or MADRS) and remission (HAMD <7 and MADRS <12). Both response and remission
rates were significantly superior with active stimulation when compared with sham (25%
versus 9% and 17% versus 6%, respectively). Additionally, an effect size of 0.48 and an NNT
of 6 for response and 7 for remission were reported. Fourteen of the 21 studies used a stricter
definition of TRD (those who failed at least two antidepressant medications [ADM] in the
current episode) and still yielded an NNT of 6 for both response and remission.
Similarly, Schutter (2009) analyzed 30 RCTs (n = 1164) in which high-frequency
stimulation over the left DLPFC was compared with sham stimulation. The results favored
active rTMS, with an overall effect size of 0.39 (95% confidence interval [CI], 0.25–0.54).
Schutter (2010) also evaluated low-frequency stimulation, and in a pooled sample of 252
depressed patients from nine RCTs, found an effect size of 0.63 (95% CI, 0.03–1.24), favor-
ing active treatment with low-frequency rTMS.
In the most recent metaanalysis, Slotema et al. (2010) pooled data from 34 RCTs, with
a total sample of 1383 patients with depression (751 received active rTMS and 632 received
sham stimulation). The results favored active rTMS, with a weighted mean effect size of 0.55
(P < 0.001). When broken down by type of stimulation, effect sizes remained medium to
large: 0.53 (P < 0.001) for stimulation over the left DLPFC, 0.82 (P < 0.001) for stimulation
over the right DLPFC, and 0.47 (P = 0.03) for sequential bilateral stimulation.
TMS versus Pharmacotherapy

TMS has not been directly compared with pharmacotherapy to date, but indirect com-
parisons are made possible by metaanalyses. Turner et al. (2008) obtained trial data for 12
antidepressant medications from the FDA (constituting 12,564 patients). The overall effect
size for published studies was 0.41. However, when all studies from the FDA database were
included, the overall effect size was 0.31. As can be seen in Figure 3.2, the efficacy of rTMS is
comparable to medications. However, there are many other reasons one might favor rTMS
over medication.
According to a recent metaanalysis, the 1-year relapse rate with maintenance ADM
treatment was 23% (Williams, Simpson, Simpson, and Nahas, 2009). However, Janicak
et al. (2010) reported a 10% relapse rate during a 6-month observational period of acute
rTMS responders, and Mantovani et al. (2012) reported a relapse rate of only 13.5% during
a 3-month observation period of the OPT-TMS remitters.
3. Effect size is the difference between the mean score of the experimental group minus that of the control group
divided by the standard deviation. It is a measure of the effectiveness of an intervention. An effect size of .80 indi-
cates that the intervention showed an approximately 50%– 80% improvement in scores (in this case, a decrease in
depression), and an effect size of .4 is associated with an approximate decrease of 50%–60%. So the effect sizes in
these analyses are clinically significant (Cohen, 1988; Morris and DeShon, 2002; Ray and Shadish, 1996).
Comparative Effect Sizes of TMS, ADM, and ECT - (HAM-D)

1
0.91
0.9 0.83
0.8
0.7
0.6 0.55
0.49
0.5 0.44
0.4
0.3
0.2
0.1
0
Overall TMS 1 ADM ≥ 2 ADM ADMs ECT
sample Failure only Failure
(n = 301) (n = 164) (n = 137) Khan, 2000 Lancet UK
Review 2003
TMS Pivotal Study O’Reardon et al., Biol Psy 2007
F I GUR E 3.2 Comparative

effect sizes of rTMS and antidepressant medications. ADM = antidepressant
medications, ECT = Electroconvulsive Therapy, HAM-D = Hamilton Depression Rating Scale.
As mentioned earlier, Avery et al. (2008) reported that remission rates in rTMS after
failure of one or two ADMs were comparable to those reported in the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) trial based on the HAMD-17 data (Rush
et al., 2006b). However, remission rates were two to three times higher after three prior
medication failures for rTMS (18.2%) versus medication change (6.9%). Additionally, in the
open-label phase of the OPT-TMS study, McDonald et al. (2011) reported a remission rate
of 30.5% (again, based on HAMD scores). The most comparable data to the STAR*D trial,
though, would be observational data from “real world” clinical practice.
In the study by Connolly et al. (2012) of 100 consecutive patients to receive rTMS in
one outpatient setting, a 35% remission rate after 6 weeks of acute treatment was reported.
Notably, the mean number of failed medication trials in the current episode was 3.4 for
this population. In addition, the most recent naturalistic study of 307 outpatients reported
remission rates of 39.9% in those who failed one or more medications during their current
major depressive episode and 34.9% in those who failed two or more medications in their
current episode (Carpenter et al., 2012).
Finally, side effects can be a significant problem for patients on antidepressant medica-
tions, leading to high discontinuation rates. STAR*D data noted discontinuation rates rang-
ing from 23.1% to 41.4% (McGrath et al., 2006; Rush et al., 2006b). Dropout rates for rTMS
are consistently less than 10% in both RCTs and obervational settings (Herwig et al., 2007;
O’Reardon et al., 2007; George et al., 2010; Connolly et al., 2012).
TMS versus Electroconvulsive Therapy

Due to the high tolerability and relatively benign side effect profile of rTMS, as well as the
convenience of being an office-based procedure that does not require anesthesia, rTMS
has become an attractive alternative to electroconvulsive therapy (ECT) for some patients
(Figure 3.3). To date, seven small trials have compared the two treatments (Grunhaus
et al., 2000; Pridmore, Bruno, Turnier-Shea, Reid, and Rybak, 2000; Janicak et al., 2002;
Grunhaus, Schreiber, Dolberg, Polak, and Dannon, 2003; Schulze-Rauschenbach et al.
2005; Rosa et al., 2006; Eranti et al., 2007).
Although rTMS was a statistical tie in six of the seven trials (Grunhaus et al., 2000,
Grunhaus et al., 2003; Pridmore et al., 2000; Janicak et al., 2002; Schulze-Rauschenbach
et al., 2005; Rosa et al., 2006), the sample sizes are too small to determine noninfe-
riority or equivalence of rTMS relative to ECT. Additionally, ECT has effect sizes
almost two-fold higher than those reported for rTMS (see Figure 3.2; UK ECT Review
Group, 2003).
A metaanalysis by Slotema et al. (2010) pooled data from six trials comparing ECT
(both unilateral and bilateral) with rTMS (high-frequency to left DLPFC). The pooled
sample tallies 215 patients (113 received rTMS and 102 received ECT). A weight effect
size of –0.47 (P = 0.004) favored ECT. Although that is an expected result, it is worth
noting that the rTMS sample received suboptimal treatment (compared with current
practice): the total number of pulses per session ranged from 1000 to 2500 and the stimu-
lation was delivered at or below MT in three out of six studies. Despite ECT’s superiority,
rTMS offers an effective alternative to patients in whom ECT is contraindicated or not
tolerated.
Predictors of Response
It is true that technique and dosing parameters have been maximized over the last several
years, but there is still a wide variety of individual response to rTMS. Lisanby et al. (2009)
Response rates with TMS and ECT

in non-psychotic Depressed Patients
100
90
80
70
60
ECT
50
TMS
40
30
20
10
0
Grunhaus, Pridmore, Janicak, Grunhaus, Rosa, Schulze- Eranti,
2000 2000 2002 2003 2006 Rauch. 2007
(N = 21) (N = 32) (N = 22) (N = 40) (N = 35) 2005 (N = 46)
(N = 30)
F I GUR E 3.3 Comparative outcomes from the ECT versus rTMS trials.
investigated predictive factors for the 301 participants from the O’Reardon et al. (2007)
study. For the acute phase of the trial, statistical analysis showed that a major depression
duration of less than 2 years and decreased evidence of antidepressant treatment resistance
were each independently associated with improved response to rTMS. In fact, the effect
size of rTMS for the subset of participants who had failed only one medication was 0.83
(but it was still 0.42 for those who had failed two to four medications in their current epi-
sode). When participants from the open-label phase were evaluated, less treatment resis-
tance was also a predictor of positive outcomes for those originally assigned to sham, but
duration of episode had no bearing on either group (sham-to-open or active-to-open).
For all open-label participants, higher baseline severity score on the MADRS and absence
of a comorbid anxiety disorder were positive predictors of response. Interestingly, older
age (often cited as a negative predictor of response) showed no significant difference for
either acute or open-label response. However, it should be noted that the study did not
include anyone aged >70 years.
In the 24-week follow-up phase of the O’Reardon et al. (2007) study, a more robust
response to rTMS in the acute trial phase was associated with a lower risk of relapse; however,
the findings of Lisanby et al. were not statistically associated with time to relapse. The authors
posited that this could be due to the small sample size or because positive predictors of acute
response might not be the same as the positive predictors of long-term response.
Subsequent studies have verified medication resistance as a negative predictor of
response (George et al., 2010; Connolly et al., 2012; Janicak et al., 2010). However, a large
naturalistic study of 307 patients showed only a moderate effect of medication resistance
on remission (39.9% of patients who failed one or fewer medications during their cur-
rent episode remitted, while 34.9% achieved remission who failed two or more medica-
tions). In addition, comorbid anxiety was not a negative predictor of response (Carpenter
et al., 2012).
Other factors that have shown greater responsiveness to rTMS are the absence of
psychotic symptoms (indirectly assumed because ECT has shown superiority to rTMS in
psychotic depression) and the absence of benzodiazepines or anticonvulsants as adjunctive
treatment (Slotema et al., 2010; Rodriguez-Martin et al., 2001; Li et al., 2011).
Clinical Effectiveness Data
With the availability of rTMS as a clinical treatment in the United States, the first
large reports of its real-world effectiveness have emerged (Carpenter et al., 2012;
Connolly et al., 2012). Although these nonresearch samples have a high degree of
treatment resistance (2.5–3.4 adequate antidepressant trials on average), results are
encouraging. Carpenter et al. (2012) pooled data from 42 clinical practices treating
unipolar patients in a current major depressive episode (n = 307). The clinical global
impression of severity scale was the primary outcome, and response and remission
rates were 58% and 37.1% at either 6 weeks or at the point of maximal clinical benefit,
respectively. These rates were congruent with those from self-report outcome mea-
sures. Those with less severe symptoms at baseline, of younger age, and showing less
treatment resistance did better. Of note, a single seizure occurred in a patient with
sleep deprivation who was also taking a combination of bupropion and stimulants
(Carpenter et al., 2012).
The Connolly et al. (2012) study differs from the Carpenter study in several
respects. The sample size is smaller (n = 100), and all patients come from a single aca-
demic medical center. It also includes cases of bipolar depression (n = 20) as well as
more patients who had failed ECT (36% versus 15%). The overall results, however, were
similar to those from the Carpenter et al. study: the response rate and remission rate, as
measured by the investigator-reported clinical global impression scale, were 50.6% and
24.7%, respectively, and congruent with self-report measures. Treatment resistance was
not found to predict treatment outcomes negatively, as might have been expected. For
those patients who previously failed ECT, the response and remission rates were 47%
and 20% at 6 weeks, suggesting that a course of rTMS in patients who failed to tolerate
or respond to an ECT course is a reasonable consideration in the treatment algorithm
(Figure 3.4).
In the bipolar subgroup (n = 20), response and remission rates were lower than in
the unipolar group (a response rate of 35% and a remission rate of 15%). This may sug-
gest that current treatment parameters for unipolar patients may be less effective in those
with bipolar depression, though caution is warranted in drawing that inference in light
of the small sample size. Overall, the study reported no seizures and a low dropout rate
of 3% due to adverse events (headache and scalp discomfort). This study also had a main-
tenance phase with about half of the sample entering 6 months of maintenance rTMS in
combination with medications. The overall durability was acceptable and comparable to
ECT maintenance, with 62% maintaining responder status at the last observation carried
forward or at 6 months.
Prior ECT Subgroup (n = 31):

TMS Response and Remission Rates
45%
Response
40%
Remission
35%
30%
25%
20%
15%
10%
5%
0%
Week 2 Week 4 Week 6
F I GUR E 3.4 Outcomes with rTMS following a prior unsuccessful trial of ECT.
Special Populations: Adolescents, Pregnant,

and the Elderly
The proven clinical efficacy of rTMS has inspired researchers to investigate it as a possible
treatment for populations where medication dosing has historically been limited due to
side effects, intolerance, or the risk of significant drug–drug interactions. Those populations
include adolescents, pregnant women, and the elderly.
The open-label study by Wall et al. (2011) of 8 adolescents had a 71% remission rate
using the Children’s Depression Rating Scale—Revised when the adolescents were treated
with 3000 pulses per day for 30 treatments. Furthermore, over the course of acute treat-
ment and for 6 months follow-up, cumulative improvement was seen and results were main-
tained. Other researchers have also shown some promising results in small trials, although
dosing parameters and sample sizes varied widely from those of the Wall et al. study. Bloch
et al. (2008) had a response rate of 30%, but only treated his patients at 400 pulses a day for
14 days, and Loo et al. (2006) had promising results for only two patients, precluding reliable
statistical analysis.
The first open-label study of rTMS in 10 pregnant women with major depression was
recently completed (Kim et al., 2011). Dosing parameters were 1 Hz at 100% MT on the
right DLPFC at 300 pulses a day for 20 days; right-sided treatment was chosen for its lower
seizure risk. The response rate was 70%, and all mothers had healthy babies with no perinatal
or postnatal complications.
Finally, Figiel et al. (1998) first reported a difference in response rates to rTMS between
those who were aged ≤65 years (56%) and those who were aged >65 years (23%) and noted
that this could be due to prefrontal atrophy seen on MRI. A recent pilot study of rTMS
in 18 patients aged 55–75 years adjusted motor threshold dosing intensity from 103% to
141% based on MRI-measured prefrontal atrophy (Nahas et al., 2004). Acute treatment was
only given for 3 weeks, but the response rate was 27%. The authors concluded that dosing
of 120% MT could overcome increased skull-to-cortex distance due to prefrontal atrophy
in most elderly patients. It is also reasonable to conclude that a longer course of acute treat-
ment might have resulted in increased response/remission rates (Avery et al., 2008; Gershon,
Dannon, & Grunhaus, 2003).
Future Directions
Clinically Modified “Accelerated” rTMS
While rTMS is a safe and effective treatment, it is not time efficient, as it requires daily sessions
lasting 30–60 minutes over a 4- to 6-week period. An interesting pilot study by Holtzheimer
et al. (2010) addressed this deficiency by giving a relatively large number of pulses (15,000)
over 2 days. rTMS at these higher dosing levels was safe and well tolerated. At day 3, results
were impressive, with a response rate of 43%. Good durability was observed at the week 3
and week 6 follow-up points (with response rates of 36% at both time points). Remission
rates reported at the three time points were 29%, 36%, and 29%, respectively. This so-called
accelerated rTMS approach may be quite helpful in patients where access or distance to an
rTMS center is problematic. It may also have implications for the future delivery of rTMS on
an in-patient basis. More research of a controlled nature is needed to validate this approach.
Even higher doses have been delivered to healthy volunteers (38,880) in 1 week (Anderson
et al., 2006), and an open label study by Hadley et al. (2011) safely delivered 30,000 pulses
per week in 20 patients, with encouraging outcomes.
Other forms of rTMS may become of increasing clinical importance in the future. An
exciting development is deep rTMS where the magnetic field has a depth of about 6 cm and
is capable of reaching frontal subcortical structures as well as the orbitofrontal cortex. At
the time of going to press, an rTMS machine by Brainsway ( Jerusalem, Israel), which is pur-
ported to deliver deep rTMS, had just received FDA clearance.
Theta burst rTMS offers the potential of having more robust effects on neuroplasticity
than standard rTMS and is in the early clinical trial phase of development. Finally, there is
great interest in combining rTMS with psychotherapy techniques such as cognitive behav-
ioral therapy and mindfulness. Such approaches conducted during rTMS sessions them-
selves may bring “on line” prefrontal cortex activation and thus have the potential to further
enhance rTMS’s efficacy.
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4
Safety of Transcranial
Simone Rossi and Jean-Pascal Lefaucheur
Introduction
Ten years after publication of the first safety guidelines for the use of transcranial magnetic
stimulation (TMS; Wassermann, 1998), a large group of experts, including neurologists,
neurophysiologists, psychiatrists, psychologists, cognitive neuroscientists, physicists, engi-
neers, and representatives from various worldwide regulatory agencies and TMS equipment
manufacturers, met in Siena, Italy, in 2008, on behalf of the International Federation of
Clinical Neurophysiology (IFCN). Their aim was to revise and update the safety guidelines
but also to consider ethical issues and recommendations for the use of TMS in research and
clinical settings. After the meeting, a consensus paper was issued and published in Clinical
Neurophysiology, the official journal of the IFCN (Rossi, Hallett, Rossini, Pascual-Leone, &
Safety of TMS Consensus Group, 2009). The main features of this consensus paper are pre-
sented in this chapter, which also addresses issues that have emerged since 2009.
Use of TMS relates to three types of adverse effects. The first type includes immediate
or short-term effects produced by the stimulation. The second concerns specific risks related
to a physiological status (children, pregnant women) or to a concurrent disease (neurological
or psychiatric disease or underlying drug treatment). The third level of risk, which is asso-
ciated with long-term chronic exposure to electromagnetic radiation, primarily concerns
operators (doctors, technicians, researchers) who use TMS on a daily basis. These aspects are
discussed in the remainder of this chapter.
Adverse Effects Related to TMS

Epilepsy
The onset of an epileptic seizure is the most serious acute adverse event that may occur when
repetitive pulsed TMS (rTMS) is used. Several cases of seizures induced by rTMS have been
Safety of T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n | 33
reported to date, mostly before safety limits were defined (Wassermannn, 1998). Considering
the large number of healthy individuals and patients who have undergone rTMS sessions
since 1998 and the small number of seizures reported, the risk of rTMS to induce seizures
could be considered very low. The likelihood of a seizure depends on the frequency of stimu-
lation, the intensity of stimulation, and the interval between two trains of stimulation (tables
detailing the safety limits for these parameters can be found in Rossi et al. [2009]). Seizures
have occurred during or immediately after rTMS trains but not long after an rTMS session
(Wassermannn, 1998). These seizures could be assigned to the parameters of stimulation
(especially because the safety guidelines were not followed; see Rossi (2013) for a review
of these cases), sleep deprivation, or proconvulsant medications. To date, no cases of status
epilepticus or epilepsy after rTMS have been reported. Finally, it is likely that some reported
“seizures” were, in fact, vagal syncopes.
Even in patients with known epilepsy, the risk of a seizure induced by rTMS, includ-
ing high-frequency rTMS, appears to be relatively low (Tassinari, Cincotta, Zaccara, &
Michelucci, 2003). It was estimated that this risk is 1.4% in the metaanalysis of Bae et al.
(2007). This may be related to the use of antiepileptic drugs, which could have a protective
effect in these patients. Recently, it has been shown that rTMS-induced seizures may origi-
nate from a cortical focus, which is different from the stimulation site (Vernet, Walker, Yoo,
Pascual-Leone, & Chang, 2012).
Tissue Toxicity
Several studies have examined brain tissue toxicity related to TMS in animal models.
Matsumiya et al. (1992) showed some potential harmful effects of rTMS (more than 100
stimuli at 2.8 Tesla) on the structural and cellular brain (cortical layers 2–6) in rats. However,
no other studies found significant morphological changes in different brain regions follow-
ing rTMS in rats (more than 10,000 stimuli at 3.4 Tesla) or rabbits (more than 1000 stim-
uli delivered at low frequency and 2 Tesla; Sgro, Stanton, & Emerson, 1991). The safety
of chronic rTMS was also confirmed in another study of both magnetic resonance imag-
ing (MRI) spectroscopy in vivo and postmortem histological analyses in rats (1000 stimuli
applied at 1 Hz for 5 days; Liebetanz et al., 2003).
Studies dealing with tissue and cellular changes associated with TMS in humans are
rare. A study of temporal lobe resected from a patient who had been exposed to rTMS
revealed no histopathological changes (Gates, Dhuna, & Pascual-Leone, 1992). Most imag-
ing studies showed no structural changes after rTMS (Nahas et al., 2000). However, diffusion
MRI, which is particularly susceptible to brain tissue damage, provided conflicting results (Li
et al., 2003; Mottaghy et al., 2003; Duning et al., 2004). Local changes in gray matter were
also reported after treatment with rTMS delivered on the superior temporal cortex daily for
5 consecutive days (May et al., 2007), which was not statistically significant after adjustment
for multiple comparisons. The significance of this finding remains to be determined because
the changes were very transient and because changes in gray matter thickness may simply
represent volumetric and circulatory effects. Further studies, including histological analyses
or morphometric imaging, should be performed to determine the possibility of cumulative
side effects on brain tissue associated with repeated sessions of rTMS.
Finally, one may wonder whether potential tissue damage relates to heating. In fact,
heating of the brain induced by a single TMS pulse is very low, <0.1 degrees centigrade
(Ruohonen & Ilmoniemi, 2002). Temperature increase depends on shape, size, and orienta-
tion of the electromagnetic field generated by the coil as well as the conductivity and prop-
erties of the surrounding tissue. Cerebral circulation generates high heat loss and provides
a safety margin, precluding brain tissue heating (Brix, Seebass, Hellwig, & Griebel, 2002).
Acoustic Trauma
The TMS pulse produces a loud noise that can exceed 140 dB (Counter & Borg, 1992). This
value is higher than the levels recommended for professional auditory security. Some authors
have observed small and transient hearing threshold increases after TMS (Pascual-Leone
et al., 1992; Loo et al., 2001). Irreversible hearing loss was reported in one patient who was
stimulated by an H coil without concomitant hearing protection (Zangen, Roth, Voller, &
Hallett, 2005). In contrast, most studies in which hearing protection was used reported no
auditory change after TMS (Pascual-Leone, Gates, & Dhuna, 1991; Folmer, Carroll, Rahim,
Shi, & Hal Martin, 2006; Levkovitz et al., 2007; Rossi et al., 2007; Janicak et al., 2008).
For anatomical and physiological reasons, young children have a higher auditory risk with
TMS. The only publication addressing this issue did not report any hearing loss in a group of
18 children who received rTMS without hearing protection (Collado-Corona et al., 2001). To
avoid any risk for hearing loss when using TMS, it is recommended that validated hearing pro-
tection (ear plugs) be used and that hearing ability (audiogram) in any person who complains
of hearing loss, tinnitus, or fullness after completion of TMS sessions be evaluated. It may be
preferable not to perform TMS in people who already have hearing loss or who receive treat-
ment with ototoxic drugs (aminoglycosides, cisplatin), except for specific indications.
Local Pain
Patients and healthy individuals should be warned that TMS is generally not pleasant and
could cause some transient local pain. In a recent metaanalysis of sham-controlled rTMS
studies to treat depression (Loo, McFarquhar, & Mitchell, 2008), approximately 28% of
patients had headache and 39% felt discomfort during active rTMS compared with 16% and
15%, respectively, with placebo rTMS. Stimulation of the scalp can be uncomfortable for
some and painful for others; this is probably related to stimulation of sensory nerve endings
on the scalp or to local repeated muscle stimulus–locked contractions, especially when TMS
is applied near the orbit. However, any migraine attack can be provoked by rTMS, even in
patients with migraine (Brighina et al., 2004).
Some researchers have explored options to reduce the local discomfort induced by
rTMS for example, through the use of topical anesthetics (Borckardt et al., 2008). However,
such an approach complicates the practice of TMS for an overall inconclusive benefit.
To conclude, local pain is common but negligible in terms of safety. In fact, in clinical
rTMS trials published to date, only a small percentage of patients discontinued treatment
due to pain induced by the stimulation (<2%). In addition, pain can be easily controlled with
minor analgesics (such as paracetamol), which are administered orally. Moreover, pain tends
to be reduced by the repetition of daily rTMS sessions ( Janicak et al., 2008).
Cognitive and Psychiatric Adverse Events

rTMS can produce undesired or potentially unwanted effects that relate to cognitive and
psychiatric adverse events. For example, rTMS can make individuals more or less effective
when performing a given task, for example, providing correct responses, reaction time, or
signal detection. These effects are usually transient, of small amplitude, and, for the most
part, do not raise specific safety issues (Rossi, Cappa, & Rossini, 2008).
The influence of rTMS on cognitive tasks has been studied extensively, frequently
based on single-session protocols with short trains of stimulation. These studies have been
performed safely in healthy volunteers without significant side effects (see supplementary
materials (table III) in Rossi et al. [2009]). A possible risk of lasting cognitive changes could
be related to the cumulative effects of repeated sessions of rTMS in the therapeutic applica-
tion for neurological diseases, especially psychiatric illnesses. In a metaanalysis of 173 articles
published between 1998 and 2004 (involving more than 3000 patients) on the application
of rTMS in nonmotor cortical areas, cognitive side effects, including fatigue, difficulty con-
centrating, and memory disorders, were reported; however, they were mild, transient, and
very rare (Machii, Cohen, Ramos-Estebanez, & Pascual-Leone, 2006). Another metaanalysis
included 39 controlled studies of rTMS in the treatment of major depression (more than
1200 patients; Brighina et al., 2004). Cognitive performance was improved by rTMS in 12
studies and deteriorated in 3 studies, and the overall analysis did not show a risk of cognitive
deterioration associated with rTMS. A large multicenter study investigated the therapeutic
effect on mood and side effects on the cognitive functions of prefrontal rTMS applied in 325
patients with major depression ( Janicak et al., 2008). No cognitive change was observed. It
remains to be seen whether repeated daily sessions of rTMS over several weeks, with mainte-
nance sessions over several months or years, leads to cumulative effects.
Particularly relevant for the application of rTMS in the treatment of depression is
the occurrence of a switch to mania in patients with bipolar depression (Loo et al., 2008).
Although a causal relationship between rTMS and the onset of the manic episode has been
suggested, this type of event is very rare (13 cases reported in 53 published studies of con-
trolled rTMS in the treatment of depression) and does not seem to occur specifically due to
active stimulation (Xia et al., 2008). The frequency of occurrence of a manic episode during
rTMS treatment is even lower than a switch to mania that occurs in the natural course of
bipolar disorder (2.3%–3.5% risk during a depressive episode; Xia et al., 2008).
The occurrence of psychotic symptoms, anxiety, agitation, or suicidal ideation has also
been reported during rTMS treatment in psychiatric patients ( Janicak et al., 2008; Zwanzger,
Ella, Keck, Rupprecht, & Padberg, 2002). However, it is not known if these symptoms were
related to stimulation or were in connection with the natural evolution of the disease being
treated. The onset of psychotic symptoms or suicidal ideation has never been described in
normal individuals during or after rTMS sessions.
In all cases reported above, rTMS-induced psychiatric adverse events were transient,
with spontaneous resolution after cessation of rTMS or effective control with pharmacologi-
cal treatment. However, patients treated with rTMS for depression or psychiatric disorders
should be informed of the unlikely possibility of developing such acute side effects, depend-
ing on the type and severity of the disease.
Biological Adverse Events
An important aspect of rTMS safety (and a potential factor that may explain some of its
effects) is the potential biological changes that are induced by stimulation on neurotransmit-
ters, hormones, and immune response.
Some aspects of synaptic transmission can be selectively changed for a given neurotrans-
mitter. This is most often seen as a desired and expected effect rather than a side effect. For
example, frontal or prefrontal stimulation can induce a marked increase in dopaminergic trans-
mission in the basal ganglia and hippocampus (Keck et al., 2000; Strafella, Paus, Barrett, &
Dagher, 2001). This can be considered beneficial for Parkinsonian symptoms (Lefaucheur
et al., 2004) but also as a psychiatric side effect at the origin of mania. Prefrontal stimulation
can also affect glutamatergic (Michael et al., 2003) or serotoninergic (Sibon et al., 2007)
transmission in different brain regions, even those that are distant from the stimulation site.
The significance of these findings is still uncertain, and there does not appear to be adverse
effects on cognitive functions.
Regarding hormone production, especially from the hypothalamic–pituitary axis,
most studies that have addressed this issue were not controlled by a placebo condition. It
has never been shown that rTMS alters the plasma level of hormones, apart from a decrease
in prolactin (Bridgers & Delaney, 1989; Wassermann et al., 1996) and a transient increase
in the release of thyroid-stimulating hormone (George et al., 1996; Szuba et al., 2001). This
result in depressed patients treated with rTMS has not been reproduced in a controlled study
(Evers, Hengst, & Pecuch, 2001). It should be noted that fluctuations in hormone levels
might be indirectly related to the therapeutic effects of rTMS protocols.
Several lines of evidence suggest lateralized cortical influence on some parameters of
the immune response in humans. For example, lymphocyte proliferation and macrophage
activation could be produced by left (dominant) hemisphere stimulation and inhibited by
right (minor) hemisphere stimulation (Neveu, Barnéoud, Vitiello, Kelley, & Le Moal, 1989).
In addition, one study showed an increase in the secretion of immunoglobulin A in saliva in
response to cortical stimulation applied to the left hemisphere but not the right hemisphere
(Clow, Lambert, Evans, Hucklebridge, & Higuchi, 2003). Further studies are needed to elu-
cidate this topic.
Autonomic Adverse Effects

Few studies have examined the influence of rTMS on the autonomic nervous system, despite
the fact that many areas of the brain are involved in the regulation of blood pressure, heart
rate, and respiration and that this may affect the safety of rTMS (Filippi, Oliveri, Vernieri,
Pasqualetti, & Rossini, 2000).
Some studies have shown that rTMS can increase blood pressure and heart rate
(Foerster, Schmitz, Nouri, & Claus, 1997) or variability (Yoshida et al., 2001) in healthy indi-
viduals. In depressed patients, rTMS treatment did not have any influence on the autonomic
nervous system (Sibon et al., 2007), apart from a tendency to improve the sympathovagal
balance (Udupa et al., 2007). Finally, rTMS could lead to changes in local vasomotor reac-
tivity in the cortical region being stimulated. This effect is mediated by the stimulation of
the autonomic nervous system. For example, cerebral vasomotor reactivity could be reduced
after active rTMS is applied to the injured motor cortex of patients suffering an acute stroke
(Vernieri et al., 2009). This potentially adverse effect on cerebral hemodynamics should be
further studied and confirmed.
Specific Adverse Effects Related to

Physiological Status
TMS in Children
A metaanalysis of more than 80 studies on the use of TMS included more than 300 children
suffering from neurological disease and 800 children without pathology (Frye, Rotenberg,
Ousley, & Pascual-Leone, 2008). No serious adverse events were reported in these studies,
but most (> 95%) were based on single-pulse TMS protocols. The safety of TMS requires
special attention in pediatrics since the risk of adverse events may be influenced by devel-
opmental changes, such as growth of the ear canal and maturation of cortical excitability.
The small relative volume of the external auditory canal generates greater resonance (Kruger,
1987) and increases the risk of injury from high-amplitude and high-frequency acoustic
noise. Also, cortical excitability is particularly high in infants, and this increases the risk of
excitotoxicity and vulnerability to seizures when TMS is used (Silverstein & Jensen, 2007).
Given the data in the literature, it has been stated that single- or paired-pulse TMS is
safe for children aged ≥2 years (Rossi et al., 2009). For children aged <2 years, no data are
available on the safety of TMS, especially relating to risk of acoustic injury. Considering the
potential risk of producing undesirable effects, it seems legitimate to not expose children to
rTMS protocols without compelling clinical reasons.
TMS and Pregnancy

Because magnetic fields attenuate rapidly with distance, it is likely impossible that a fetus
would be directly affected by cortical stimulation with a coil applied to the scalp. Currently,
few studies have reported the effectiveness of treating depression in pregnant women with
prefrontal rTMS without any side effects reported in children born (Nahas et al., 1999;
Klirova, Novak, Kopecek, Mohr, & Strunzova, 2008). Nevertheless, it seems justified to con-
sider the risk/benefit ratio of rTMS in each case before considering use during pregnancy.
Lumbar spinal magnetic stimulation is formally discouraged.
Specific Adverse Effects Related to

Concurrent Disease or Treatment
Influence of Disease
The effects of rTMS depend on the state of excitability of the cortex targeted, therefore, it is
important to consider the influence of diseases on cortical excitability. For example, depres-
sion causes changes in functional activation of the dorsolateral prefrontal cortex depending
on the hemisphere stimulated. Kimbrell et al. (1999) showed that the basal level of activation
of the dorsolateral prefrontal cortex could predict the likelihood of a therapeutic response to
rTMS applied in this region. These relationships may have an impact on the desired thera-
peutic effects as well as on the occurrence of side effects.
The degree of excitability of the cortical area stimulated and its functional connectivity
as well as the associated synaptic patterns may influence the therapeutic efficacy of a specific
rTMS protocol (Silvanto & Pascual-Leone, 2008). Referring to the Bienenstock–Cooper–
Munro model of plasticity, brain stimulation should be more effective at potentiating syn-
aptic transmission if the basal level of postsynaptic activity is low and brain stimulation
should be more effective at depressing synaptic transmission if the basal level of postsyn-
aptic activity is high (Bienenstock, Cooper, & Munro, 1982). The concept of metaplastic-
ity (Abraham & Bear, 1996) explains the discrepancies between the effects achieved by a
protocol of using rTMS in patients compared to healthy individuals. Thus, high-frequency
rTMS of the motor cortex enhances facilitatory corticospinal output in healthy individu-
als, whereas it restores intracortical inhibition, which is reduced at baseline, in patients with
neuropathic pain (Lefaucheur, Drouot, Ménard-Lefaucheur, Keravel, & Nguyen, 2006).
Other types of paradoxical responses to rTMS protocols have been reported, for example,
in schizophrenic patients (Fitzgerald et al., 2004). This is why it is unreasonable to apply a
simplistic, dichotomous view of rTMS (excitatory high-frequency rTMS versus inhibitory
low-frequency rTMS) in pathological conditions according to what is observed in healthy
individuals. Priming paradigms (by drug or cortical stimulation) are thus possible to modify
an expected response to a specific rTMS protocol.
A recent review addressed the safety of rTMS in patients with pathologically positive
sensory phenomena (Muller, Pascual-Leone & Rotenberg, 2012), a topic that was not cov-
ered specifically in the last available guidelines (Rossi et al., 2009). Among these are tinnitus,
auditory and visual hallucinations, and pain syndromes, all conditions that are potentially
linked to a pathological increase of cortical excitability in sensory or associative brain regions.
In a sample of 1815 patients, adverse events were generally mild and occurred in 16.7% of
patients. Seizure, which was the most serious adverse event, occurred in three patients, with
a 0.2% crude per-individual risk. The second most severe adverse event involved aggrava-
tion of sensory phenomena, occurring in 1.5% of patients, primarily those with tinnitus who
presented hyperacusis. This is a transient finding that has been reported previously (Rossi
et al., 2007; Lefaucheur et al., 2012). Results of the metaanalysis suggest that rTMS in these
patients is reasonably safe and well tolerated (Muller et al., 2012), with a risk of developing
side effects that does not differ from that in studies done with rTMS on other neuropsychi-
atric disorders.
Also, it has been proposed that neuromodulation via rTMS is a successful way to allevi-
ate symptoms in posttraumatic brain injury patients (Demirtas-Tatlidede, Vahabzadeh-Hagh,
Bernabeu, Tormos, & Pascual-Leone, 2012), another topic not covered in the 2009 guide-
lines. Possible concerns related to the use of rTMS in these patients are the higher risk of
seizures following head trauma as well as factors related to a distorted conductance and mag-
nitude of the electric current being induced in cortical regions due to the skull damage and
fractures. Indeed, skull injuries significantly modify the distribution of the induced currents,
which may become concentrated toward the edges of large skull defects, depending on the
combination of type of stimulation and nature of the defect (Madhavan, Weber II, & Stinear,
2011). Of course, in addition to the presence of skull defects, craniotomy with placement
of skull plates might add another potential risk for application of rTMS in traumatic brain
injury patients (Rotenberg et al., 2007; Rotenberg & Pascual-Leone, 2009). Today, available
safety data of rTMS on these patients are still very limited. A detailed safety assessment in
a single patient with severe traumatic brain injury reported a lack of adverse events follow-
ing the application of 300 paired TMS pulses per day over the right dorsolateral prefrontal
cortex for 6 weeks (Louise-Bender Pape et al., 2009). However, in another patient with trau-
matic brain injury (Cavinato, Iaia, & Piccione, 2012), a protocol of 20 Hz rTMS applied
for 10 minutes per day over the left dorsolateral prefrontal cortex led to the occurrence of
a partial and secondarily generalized tonic–clonic seizure 3 hours after the fourth session
of rTMS. The value of rTMS in the recovery of awareness in patients with comatose state
remains to be investigated. However, in such an application, safety is a key issue, and careful
monitoring is recommended.
Influence of Concomitant Medication

Some drugs increase the risk of seizure because they lower the seizure threshold. This may
be implicated in the majority of rTMS-induced seizures reported in the literature (Rossi
et al., 2009). Drugs that significantly lower the seizure threshold and those that significantly
increase the risk of rTMS-induced seizure include imipramine, amitriptyline, doxepin, nor-
triptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphet-
amines, cocaine, ecstasy, phencyclidine, ketamine, gamma-hydroxybutyrate, alcohol, and
theophylline. When these substances are used, rTMS should be performed with caution.
Other drugs moderately lower the seizure threshold and are less of an obstacle to the
application of rTMS. These include mianserin, fluoxetine, fluvoxamine, paroxetine, sertra-
line, citalopram, reboxetine, venlafaxine, duloxetine, bupropion, mirtazapine, fluphenazine,
pimozide, haloperidol, olanzapine, quetiapine, aripiprazole, ziprasidone, risperidone, chlo-
roquine, mefloquine, imipenem, penicillin, ampicillin, cephalosporins, metronidazole,
isoniazid, levofloxacin, cyclosporine, chlorambucil, vincristine, methotrexate, cytarabine,
carmustine, lithium, anticholinergic, antihistaminic, and sympathomimetics.
The actual risk depends on a variety of factors such as dose, interactions with other
medications, and changes in prescription (recent increase or decrease of the dose). Thus, the
withdrawal of certain substances (alcohol, barbiturates, or benzodiazepines) represents a sig-
nificant increased risk of seizure. Similarly, sleep deprivation and extreme fatigue are also
conditions that result in a significant lowering of the seizure threshold.
Implanted Devices
A potential safety hazard to consider when applying rTMS in patients with an implanted deep
brain stimulation (DBS) system is the induction of significant voltages in the subcutaneous
leads in the scalp. This could result in unintended electrical currents in the electrode contacts
used for DBS. The situation may be exacerbated by coiling of the electrode lead into several
loops near the electrode insertion point in the skull (Rossi, et al., 2009). Voltages as high as
100 V, which can result in currents as high as 83 mA, can be induced in the DBS leads by a
TMS pulse. These currents can expose patients to potential tissue damage, which can occur
when the internal pulse generator (IPG) is turned on or off (Deng, Lisanby, & Peterchev,
2010). It is clear that caution is required when using TMS in patients with DBS electrodes.
In addition, the presence of implants, such as DBS electrode or aneurysm clip, in
the field of TMS poses real problems in terms of heating that may cause irreversible tissue
damage (Matsumi et al., 1994). In contrast, titanium plates have a lower conductivity and
do not seem to be an obstacle to use of TMS, especially because they are not ferromagnetic
(Rotenberg et al., 2007).
Another problem is the possible (de)magnetization of intracranial implants. The elec-
tromagnetic pulse generated by the TMS can cause damage or malfunction in the internal
circuits of electronic implants that are <10 cm from the TMS coil (Kumar, Chen, & Ashby,
1999). At >2 cm, electronic circuits can be damaged permanently. In addition, the TMS pulse
can activate or deactivate these systems unexpectedly or cause them to move. TMS is certainly
dangerous for patients with cochlear implants, which include a cochlear electrode, an antenna,
a magnet, and a microchip implanted under the scalp, and are particularly sensitive to electro-
magnetic fields. These implants are an absolute contraindication to use of TMS.
DBS electrodes present a different challenge than cochlear implants. In fact, a number
of TMS studies have been conducted in patients with electrodes implanted in the peripheral
or central nervous system (see supplementary materials (table I) in Rossi et al. [2009]). Most
of these studies were based on single- or paired-pulse TMS and rarely consisted of rTMS pro-
tocols. Some of these studies were conducted within a few days after electrode implantation
while they were not yet connected to the IPG. Two studies on dystonic patients treated with
pallidal stimulation (Kühn, Trottenberg, Kupsch, & Meyer, 2002) and Parkinsonian patients
treated with subthalamic stimulation (Hidding et al., 2006) showed that use of TMS induced
a current in the DBS system at the origin of motor responses in these patients. However, no
adverse events were reported, except for the generation of unexpected motor responses.
Thus, TMS can be performed in patients with an implanted DBS electrode if there are
scientifically or medically compelling reasons to use this type of stimulation. The distance
between the TMS coil and the IPG must be maximized, that is, it should be preferentially
>10 cm and at least not <2 cm. Cortical stimulation with a TMS coil applied to the scalp can
be considered safe in individuals with vagus nerve stimulator, spinal cord stimulator, or cardiac
pacemaker if material that is >10 cm thick is placed over the system located in the neck, chest,
or abdomen to prevent activation of the TMS coil near the system and any resultant accidental
stimulation. These implanted devices remain as contraindications to performing MRI; this fact
excludes the practice of image-guided navigated TMS in these patients.
Chronic Exposure to TMS: The Case

of Operators
A single rTMS session represents a very low exposure to electromagnetic fields in terms of
intensity and duration. A 2-week long rTMS treatment course (eg, treatment of depres-
sion) leads to a total duration of exposure to electromagnetic fields of less than 20 minutes,
which does not have any consequence in terms of health risk (Loo et al., 2008). However,
safety related to chronic exposure to magnetic fields generated by rTMS is very different
for operators (doctors, technicians, and researchers) because these individuals are potentially
exposed several hours a day for years to TMS. Maximum tolerable values for exposure to
electromagnetic fields for workers have been defined in a European directive, taking into
account the immediate danger. However, long-term effects were excluded from the scope
of this directive. In fact, only one study has been conducted on safety for TMS operators
(Karlström, Lundström, Stensson, & Mild, 2006). This study used a MagPro stimulator
(MagVenture), a figure-8 coil, and a stimulation intensity ranging from 60% to 80% of the
maximum stimulator capacity. Under these conditions, the safety limits for workers exposed
to electromagnetic fields diminish at a distance of about 70 cm from the coil. This means
that, in theory, TMS operators must keep their body more than 70 cm away from the center
of the coil to eliminate risk. This is achieved if the coil is placed at arm’s length. However, the
potential risk of longer-term daily exposure for TMS operators, that is, months or years of
exposure to relatively close electromagnetic fields (even of low intensity), should be evaluated
in order to define proper safety limits with respect to type of magnetic stimulator, type of
coil, frequency, and intensity of stimulation.
Safety Issues for Various Stimulation

Parameters
In clinical applications, various rTMS parameters, such as intensity and frequency of the
stimulation, duration of the train and of the interval between trains, total number of trains
and TMS pulses per session, and number of sessions per week for the initial treatment course
and possibly for maintenance therapy, must be determined with great care. Safety limits have
been defined, especially for the prevention of epileptic risk. However, it should be empha-
sized that these limits were set for relatively small samples of normal individuals, not for
patients with neurological or psychiatric diseases.
Field Type
The morphology of the induced field is less frequently taken into account than other param-
eters of stimulation. Stimulators used for rTMS typically generate biphasic pulses, whereas
single-pulse TMS is usually based on monophasic pulses. New prototype stimulators are
capable of changing the pulse shape, width, and duration. These pulse waveforms differ in
their efficacy to produce axonal depolarization. Recent evidence shows that monophasic
pulses applied repeatedly are more effective in modifying cortical excitability than biphasic
pulses (Arai et al., 2005, 2007; Sommer et al., 2006). This suggests that safety guidelines
should be established specifically for monophasic rTMS. However, this type of stimulation is
currently very limited in terms of intensity and train duration because of equipment heating,
at least with current magnetic stimulators.
Stimulation Intensity
Stimulation intensity is usually expressed as a percentage of rest motor threshold (RMT),
which is the minimum intensity required to elicit an electromyographic (EMG) response
(motor-evoked potential [MEP]) of at least 50 µV, with a probability of 50% in a hand
muscle at rest (Rossini et al., 1994). RMT can also be determined by observing clini-
cal motor responses (finger movement) rather than recording MEP. This visual method
overestimates the minimum intensity required to activate the motor cortex and therefore
potentially increases the danger of TMS. To quantify the “dose” actually administered at
the cortical level, the calculation of the induced current density in individual brains would
be more appropriate; however, this type of calculation is difficult to perform reliably. Some
navigation systems offer an estimate of the current density that is based on head model and
type, position, and orientation of the TMS coil. Although knowledge of the induced current
density is laudable, it is not enough to determine the safety of the stimulation at biological
and behavioral levels.
Coils for Deep Stimulation

A recent technological advance in TMS is the H-shaped coil, which stimulates deeper than
conventional figure-8 coils. Recent studies have addressed the safety of these coils in small
groups of patients with bipolar depression treated daily for 4 weeks (Harel et al., 2011) and
after rTMS performed as continuation therapy for 18 weeks (Harel et al., 2012). Although
no significant adverse effects were found, such promising results should be replicated by
independent researchers without commercial relationships with coil manufacturers. A recent
study updates the electric field focality and depth of penetration of various TMS coils (Deng,
Lisanby, & Peterchev, 2012).
Stimulation Frequency and Duration of Trains and

Intertrain Intervals
Rossi et al. (2009) provide tables that show the maximal train duration and minimal inter-
train interval that can be safely used according to stimulation frequency for intensities
ranging from 90% to 130% of RMT. These tables can be used to determine parameters of
stimulation to be used in any rTMS study with a good safety margin. The application of stim-
ulation parameters outside these limits can be considered in patients with specific objectives,
but a priori not in healthy individuals. Moreover, it is likely that these limits can be exceeded
safely in patients receiving anticonvulsant drugs. Conversely, greater caution should be taken
in patients who have a lowered seizure threshold.
These safety settings derive from studies of rTMS applied to the motor cortex in
healthy individuals. Since the threshold of postdischarge induction is lower for the motor
cortex than other cortical regions, it is reasonable to assume that these parameters are also
safe for applications of rTMS in cortical areas outside the motor cortex. However, the exact
relationship between the excitability of the motor cortex and nonmotor regions has not been
determined.
Cumulative Doses
In the treatment of depression, recent protocols tend to be based on more pulses per session,
more sessions, and longer duration of maintenance therapy, leading to a significant increase
in the cumulative dose of TMS pulses delivered to the patient. For example, in the study by
Hadley et al. (2011), patients with treatment-resistant depression received daily 5000–9000
stimuli per session of left prefrontal rTMS at 120% RMT for a prolonged time. During this
treatment period, one patient received 1,243,500 stimuli within 2 years. Although this study
was outside the safety margins for rTMS application, with more than twice the number
of stimuli per day that was previously shown to be safe (Anderson et al., 2006), no serious
adverse events occurred, including no seizure.
New Paradigms of Stimulation

Among the new rTMS protocols proposed to date, theta burst stimulation (TBS) is fre-
quently used both in research and for clinical applications. It should be noted that TBS
protocols have not been standardized (the number of pulses and the inner frequency of the
TBS train as well as the repetition frequency of the trains vary between studies (see Table 6
published by Rossi et al. [2009]). However, stimulation frequencies used for TBS are higher
than those used for “conventional” high-frequency rTMS, resulting in a potentially higher
risk of seizure. Oberman et al. (2011) performed a metaanalysis of 67 TBS studies (1040
individuals, including 225 patients, for approximately 4500 TBS sessions). Most individu-
als (632) received TBS over the primary motor cortex, but other brain regions were stimu-
lated, including the prefrontal cortex; supplementary motor area; frontal eye field; parietal,
temporal, and occipital cortical regions; and cerebellum. Overall, the risk for adverse
events during TBS was estimated to be 1.1% and that of seizure was 0.02%. Adverse events
induced by TBS were comparable to those commonly described for conventional rTMS,
both in terms of severity and incidence (see Table 1 in Rossi et al. [2009]). Adverse events
included mild headache, mild discomfort due to cutaneous sensation and neck muscle con-
traction, hyperacusis in tinnitus patients, nausea, and vagal responses. The most common
TBS-induced side effects were transient headache and neck pain, which occurred in <3%
of the individuals receiving TBS, while these adverse events were reported in up to 40%
of patients undergoing high-frequency rTMS (Rossi et al., 2009). This probably results
from a difference in stimulation intensity, which is usually lower for TBS (80% of active
motor threshold [AMT], which is determined in a contracted muscle and therefore lower
than RMT) than for conventional rTMS protocols (ranging from 90% to 120% of RMT).
However, one case of epileptic seizure induced by a TBS protocol was reported in a healthy
volunteer (Oberman & Pascual-Leone, 2009). In that case, stimulation intensity was set at
90% of RMT, an unusually high value compared to the most often used intensity of 80%
of AMT.
Priming Strategies
According to the concept of “metaplasticity” (Abraham & Bear, 1996), rTMS can be pre-
ceded by another cortical stimulation protocol or drug intake to optimize its efficacy. Such a
priming strategy may considerably modify the safety of a given rTMS paradigm. Among the
priming techniques, various forms of transcranial electrical stimulation can be considered
(eg, transcranial direct current stimulation, transcranial alternating current stimulation, or
transcranial random noise stimulation). Whether the interaction between such types of cor-
tical stimulation and rTMS expose individuals to a higher risk of seizures or other side effects
needs to be determined.
Neuroimaging Environment
The practice of TMS in a neuroimaging environment has been the topic of several stud-
ies and is likely to develop in the future (Bestmann, Ruff, Driver, & Blankenburg, 2008;
Siebner, Peller, & Lee, 2008). When TMS is performed in the MRI room, specific safety
issues related to the static magnetic field of the MRI machine and radio-frequency pulses
must be addressed. Also, all ferromagnetic materials must be removed from the stimulating
coil or be perfectly anchored. The wiring of the coil should be well shielded to prevent inad-
vertent stimulation during MRI. Some coils are manufactured to meet the requirements for
dedicated use in an MRI environment, ensuring only the integrity of the coil and its proper
functioning. To date, studies have been conducted with field strengths of 1.5, 2, and 3 Tesla.
No data are available for higher field intensities.
Monitoring the Safety of TMS

It has been proposed that the risk inherent to rTMS, including epileptic risk, be controlled
by applying different surveillance methods. Although these methods cannot be used in rou-
tine practice of rTMS, they are recommended for studies based on TMS protocols for which
safety is not known because of their novelty. Two methods have been proposed for detecting
early signs of increased cortical excitability or spread of cortical activation that might lead to
a seizure: electromyography (EMG) and electroencephalography (EEG).
EMG Monitoring
In studies where rTMS is not expected to generate MEPs (motor cortex stimulation below
motor threshold or stimulation of a nonmotor area), the session can be monitored by record-
ing EMG in a hand muscle contralateral to rTMS. The occurrence of EMG activity during the
stimulation reflects an increase in cortical excitability reaching the motor cortex. In studies
where the stimulus is supposed to produce hand MEPs, EMG monitoring can be performed
on a proximal arm muscle such as the deltoid muscle. If EMG recording is not available,
individuals or patients can be monitored by a qualified person. However, this method is less
sensitive and objective than EMG recording (Lorenzano et al., 2002). The occurrence of
muscle twitches related to the stimulation may also provide an indication of cortical activa-
tion spreading.
EEG Monitoring
Theoretically, EEG is the most appropriate method for detecting a pre-epileptic increase in
cortical excitability during rTMS. Indeed, EEG postdischarge after cessation of cortical stim-
ulation is considered to be the first indicator of a seizure (Ajmone-Marsan, 1972). A number
of combined EEG–TMS studies have been published to date, and these are outlined in the
chapter by Daskalakis. Changes induced by TMS on EEG activity, especially on oscillatory
activities, have been demonstrated for a variety of cortical targets, even in the absence of clini-
cal or behavioral consequence (Rossi et al., 2000; Hansenne, Laloyaux, Mardaga, & Ansseau,
2004; Holler, Siebner, Cunnington, & Gerschlager, 2006). At the end of an rTMS session,
these changes may last for 20–70 minutes (Enomoto et al., 2001; Tsuji & Rothwell, 2002;
Thut et al., 2003). However, EEG monitoring is not feasible in routine practice of rTMS,
primarily because it requires expensive equipment that makes EEG recording possible during
rTMS without artifacts caused by magnetic pulses.
If EEG deteriorates, it can be difficult to determine whether this degradation is really
predicting that a seizure will occur or not (Thut & Pascual-Leone, 2010). In addition, even if
EEG deterioration leads to cessation of rTMS, the post effect can be such that the crisis will
still occur. Also, given the low incidence of seizures triggered by rTMS, the inconvenience of
performing EEG during rTMS, and its poor prediction relevance, currently it is not possible
to recommend EEG monitoring in research protocols of rTMS. The realization of a standard
EEG recording before an rTMS session also does not seem useful, sensitive, or specific for
predicting the likelihood of a seizure.
Management of Syncopes and Seizures

Each laboratory involved in rTMS practice should establish detailed procedures for dealing
with syncope or seizure, and each team member must be familiar with these procedures. In
addition, a readily accessible emergency cart must be available in laboratories that perform
protocols with high epileptic risk.
Seizures induced by TMS are usually of short duration, requiring no specific drug
treatment and causing no durable effects. Indeed, the occurrence of status epilepticus after
a session of rTMS has never been described. Individuals or patients who have experienced
a seizure triggered by rTMS should be informed that they have no increased risk of seizures
compared to their previous situation. For some people, however, the potential psychologi-
cal burden of having experienced a seizure can be significant and should not be ignored or
minimized. Patient information and consent forms should clearly discuss the possibility of
a seizure. Also, investigators must ensure that the individuals or patients understand the
implications.
Summary of Contraindications
and Precautions
The only absolute contraindication of TMS is the presence of ferromagnetic material or
implanted devices in close contact with the coil (less than 2 cm) because of the risk of dis-
placement or malfunction. Therefore, regarding cortical stimulation (coil applied to the
scalp), contraindications are cochlear implants or other intracranially implanted hardware.
When implanted cortical stimulation or DBS systems are present, TMS protocols are not
recommended (especially rTMS protocols) or require specific justification or indication.
However, cortical TMS may be considered in cases of cardiac pacemaker or vagus nerve or
spinal cord stimulation if material thicker than 10 cm is placed over the implanted genera-
tor. Pregnant women, children (aged >2 years), and patients with hearing disorders require
specific justification or indication for rTMS.
There is no proven risk of using single- and paired-pulse TMS. The primary risk associ-
ated with rTMS is epilepsy. Auditory risk can be minimized by using hearing protection, as
previously discussed. In this context, conditions that could increase the risk of inducing a
seizure are related to the stimulation protocol (depending on various stimulation parameters,
including intensity, frequency, and train or intertrain interval duration), disease, and patient
condition (such as personal history of epilepsy, focal cerebral lesion, drug intake or removal
that lowers the seizure threshold, or sleep deprivation).
A self-administered questionnaire can be used to select candidates for rTMS and to
exclude those with a higher risk of adverse events. The following questions, which differ
somewhat from those in the previous questionnaire (Rossi et al., 2009), should be asked:
1. Have you ever received TMS in the past? If yes, have you experienced any side effect?
2. Have you ever undergone MRI examination in the past?
3. Have you ever had a seizure in the past? If yes, can you describe on what occasion.
4. Have you ever had a syncope in the past? If yes, can you describe on what occasion.
5. Have you ever had a severe head injury (that is to say, followed by a loss of consciousness)?
6. Are you pregnant or could you be pregnant?
7. Do you have hearing problems? If yes, of what type?
8. Do you have cochlear implant?
9. Do you have any metal particles in the brain or skull? If yes, of what type?
10. Do you have a neurostimulator implanted in your body? If yes, of what type?
11. Do you have an implanted device for drug delivery?
12. Do you have a cardiac pacemaker?
13. Do you take drugs? (Please list them)
Conclusions and Regulatory Aspects

TMS/rTMS for diagnostic, therapeutic, and research purposes has developed considerably
in recent years, and it is likely that this will continue and intensify in the coming years, partic-
ularly regarding therapeutic aspects. Safety rules for use of this technique in different applica-
tions or indications must be established. One limitation of these safety recommendations is
that they are based on limited experimental data that were, in most cases, obtained in small
populations of healthy individuals and often in response to stimulation of the motor cortex.
One must be careful in extrapolating these results to the stimulation of nonmotor cortical
areas in patients with neurological or psychiatric disease and concomitant medication. In
addition, new paradigms of rTMS are constantly being proposed, and safety data for these
new paradigms are limited and standardization is often far from being established. Finally, it
is crucial that the safety of operators who use TMS daily be evaluated.
Thousand of patients have undergone TMS in a variety of settings, from basic research
studies performed in academic centers to clinical application in private clinics. The expanded
use of TMS often extends beyond solid scientific evidence, and careful assessment of the
existing knowledge is important. An updated review of all current applications of rTMS in
neurology, neurorehabilitation, psychiatry, and otolaryngology, together with an attempt to
classify the level of evidence of the various indications, can be found in the recently pub-
lished French guidelines for use of TMS (Lefaucheur et al., 2011). Several TMS protocols
and devices have been approved in a few countries for specific clinical/therapeutic uses. In
the United States, the US Food and Drug Administration approved use of the Neuronetics
magnetic stimulator for treatment of patients with major resistant depression. The treat-
ment of depression by rTMS has been also approved in Canada and Israel. Finally, in 2011,
the Federal Council of Medicine in Brazil approved use of rTMS for treatment of major
depression and auditory hallucinations in schizophrenia. Safety guidelines should follow the
expected development of clinical indications of rTMS therapeutic protocols in the future.
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5
Patient Selection and

Management
Peter B. Rosenquist and W. Vaughn McCall
Introduction
Clinicians who care for patients with treatment-resistant depression (TRD) have a number
of challenges, not the least of which are determining what treatments to offer and in what
order and ensuring that these treatments are administered using evidenced-based proto-
cols. While this chapter focuses primarily on transcranial magnetic stimulation (TMS),
it is written from the perspective of the ideal “full-service” mental health provider. This
type of provider offers a full range of services and US Food and Drug Administration
(FDA)–approved treatments, including assessment, psychotherapy, pharmacotherapy, TMS,
electroconvulsive therapy (ECT), and vagus nerve stimulation (VNS), for patients with
mood disorders.
Which patients are ideal candidates for TMS and what are the factors that determine a
successful course of TMS? The outcome of TMS is determined to varying degrees by patient
factors (ie, severity of illness, adequacy and resistance to prior therapeutic trials) and by the
TMS technique used. In this chapter we explore these factors as they relate to where TMS
should be positioned in the range of therapeutic interventions.
Consultation
While TRD patients may be self-referred, more often their regular treating psychiatrist who has
exhausted the available pharmacologic or psychotherapeutic options refers them. In the face of
complex presentations in individuals with TRD, it should be evident that caring for severe and
treatment-resistant conditions begins with a careful evaluation. Competent practicing clinicians
have learned to gather history, assess mental status, and construct a formulation and plan.
Table 5.1 lists the essential elements for the assessment, which are used to define
the patient’s condition in such a way as to make very clear the basis for decision-making.
Questions to be presented include the following: why this treatment, at what frequency or
P at i e n t S e l e c t i o n and M a n ag e m e n t | 53
TABLE 5.1 Essential Elements in a Framework for Assessment
Element Considerations
Diagnosis The primary diagnosis

Comorbid diagnoses that may affect clinical response
Documentation of past treatment Treatments that have been tried
Adequacy of therapeutic trials
Number of failed trials
Adverse effects associated with prior treatments
Measurement of symptoms Baseline severity of illness
Monitoring of response
Measurement of adverse effects Systemic
Psychiatric
Cognitive
Multiple frames of reference Provider rating
Patient rating
Caregiver rating
intensity, when to stop or amend the treatment plan, how to proceed at the point of achiev-
ing response or remission, and with what alternatives?
Diagnosis
The primary diagnosis is an essential component of the FDA’s labeled indications for a given
treatment. The vast majority of patients receive neuromodulation therapies for the treat-
ment of a major depressive disorder (MDD), and this constitutes the common denominator
of labeled indications. Antidepressant medications and psychotherapy, the most common
first-line therapies for depression, are effective for many patients; however, a sizable minority
of patients (10%–40%) are refractory to these interventions.
Of considerable importance in treatment selection and planning are medical, psychiatric,
and psychosocial comorbid conditions that may affect the efficacy or safety of a given treat-
ment. MDD with comorbid axis I disorders is associated with more chronic course, functional
impairment, and treatment resistance (Petersen et al., 2001). Similarly, axis II personality disor-
ders, specifically borderline personality, are associated with a poor prognosis in the treatment of
MDD (Newton-Howes, Tyrer, & Johnson, 2006), although there is insufficient evidence specifi-
cally for neurostimulation therapies in the treatment of personality disorders (Gescher, Cohen,
Ruttmann, & Malevani, 2011; Alino, Jimenez, Flores, & Alcocer, 2010).
Evaluation of Past Treatment

Ideally, a record of prior treatments is available to construct a chronology of doses, durations,
and combinations of medications, psychotherapies, and neuromodulation trials. Despite the
probability of missing data, there are a number of useful tools that can be used to systematize
this history-taking and characterize the degree of treatment resistance in terms of the number of
failed trials (Ruhe, van Rooijen, Spijker, Peeters, & Schene, 2012). Recognition memory typi-
cally outstrips spontaneous recall, so a checklist of medications given to the patient prior to and
reviewed during the initial visit will help in this evaluation. It can be a challenge to define specific
episodes of care for some patients. However, a simple timeline similar to the National Institute
of Mental Health Life Chart Manual (Leverich & Post, 1993) can be used to clarify the onset of
the present illness and the adequacy of each medication trial.
The antidepressant treatment history form (ATHF; Prudic, Sackeim, & Devanand,
1990) has been used in clinical trials (including the pivotal trials in TMS) to define the
degree of treatment resistance by the number of failed adequate medication trials in the pres-
ent episode. Because the ATHF systematically evaluates multiple sources of data on prior
treatment, it can be somewhat cumbersome to use in its fully validated form. However, the
ATHF is a helpful point of reference when summarizing treatment resistance, for example,
ATHF level 2 refers to a patient’s depression that was not relieved by two antidepressants
administered at an adequate dose and duration.
As discussed in Chapter 3, the FDA-labeled indication for TMS is restricted to patients
who have failed only one adequate trial of antidepressant medications (ADMs) during the
present depressive episode (O’Reardon et al., 2007), and repetitive TMS (rTMS) is less
effective in patients with multiple antidepressant failures (Lisanby et al., 2009). The clinician
should assess the patient’s degree of treatment resistance in order to adequately define the
potential treatment response, given the fact that patients with significant TRD (i.e., failure
of two or more antidepressant treatments in the current episode) are being treated off label.
Chapter 3 outlines the data in primarily open-label trials that support the use of rTMS is
TRD. However, the off-label use of rTMS should be discussed prior to treatment in patients
who have failed multiple antidepressant trials.
Treatment Planning
Tables 5.2 and 5.3 outline the advantages and disadvantages of TMS compared with other
antidepressant therapies. Pharmacotherapy and psychotherapy are included in the table,
most often as first-line treatments. ECT and VNS are usually reserved for more severely ill or
treatment-resistant patients.
When discussing available options, major treatment considerations include patient fac-
tors such as diagnosis, severity of illness, psychiatric comorbidities, and general medical con-
ditions that may be relative contraindications for a given treatment. Other advantages and
disadvantages derive from specific characteristics of the treatment. These include intrinsic
aspects such the range of efficacy, rate of response in a clinical setting, onset and durability
of therapeutic benefit, and side effects. In addition, practical considerations such as length of
an adequate trial, availability of the treatment, cost, standardization of the treatment across
providers, and caregiver considerations should be discussed.
Range of Efficacy
While TMS has shown promise in a number of neuropsychiatric conditions (Slotema,
Bloom, Hoek, & Sommer, 2010), the FDA-approved indication is for the treatment of
moderately treatment-resistant MDD. By contrast, there are data that support the efficacy of
ECT in a number of severe psychiatric conditions, including MDD, manic episodes, MDD
with psychotic features, catatonia, and schizophrenia (American Psychiatric Association
Task Force, 2001). VNS is approved for the treatment of epilepsy and MDD. In addition,
TABLE 5.2 Comparative Advantages and Disadvantages of Antidepressant Therapies—Clinical Efficacy and Tolerability
Parameters of Efficacy and ECT TMS VNS Drug Therapy Psychotherapy

Tolerability (CBT, IPT)
Indications MDD MDD MDD Multiple drug classes Nonspecific and broad
Bipolar mania Epilepsy and combinations; spectrum efficacy; can
Catatonia can be directed be directed toward
Schizophrenia toward specific specific symptoms
symptoms
Severity of Moderate to Moderate Severe Mild to severe Mild to moderate
illness severe
Antidepressant response* 70%–87.8%1 42.5%–58%1-3 33.1%–54.2%1 51%–6-52.4%1 26%1
in open-label treatment
*(Response as defined by
50% decrease in Hamilton
Depression Rating)
Onset of benefit 1–3 weeks 2–4 weeks 3–12 months 2–4 weeks Highly variable
Durability 63% at 6 months 2
59.4% 4
63% at 12 months 57.4%–59.4% at 39% at 26 weeks1
rate of sustained response (monotherapy, remission) (response, combination 61%–65% at 24 months 7 months1
or remission of pharmacotherapy plus (response, combination of
TMS) pharmacotherapy plus VNS)1
Systemic adverse effects Yes Rare Rare Yes No
References Rasmussen, 2011; Avery et al., 2008; Sackeim et al., 2007 Rush et al., 2011 Peeters et al., 2013
Kellner, 2006 Connolly et al., 2012;
Carpenter et al., 2012;
Janicak, 2010
Abbreviations: CBT cognitive behaviour therapy; IPT interpersonal therapy; ECT, electroconvulsive therapy; MDD, major depressive disorder; TMS, transcranial magnetic stimulation; VNS, vagus nerve
stimulation.
TABLE 5.3 Comparative Advantages and Disadvantages of Antidepressant Therapies—Practical Considerations
Practical Considerations ECT TMS VNS Drug therapy Psychotherapy

(CBT, IPT)
Adequate trial 8–12 treatments 20–30 treatments 6 months Daily 6–12 weeks 12–16 sessions
over 2–5 weeks over 4–6 weeks
Start-up cost to provider $30,000–$40,000 Device: $60,000–$80,000 – – –
Cost to payer $2000–$3000 per session; $200–$500 per session; $25,000–$40,000 for Highly variable based on $1600–$3200
course, $12,000–$36,000 course, $4000–$15,000 device and surgery pharmacy benefit and number
and expense of medications
Availability of the ++ ++ + ++++ +++
treatment Varies by locale; generally Varies by locale; Significant barriers; Widely available; multiple Widely available; multiple
hospital based; some case ambulatory; case load requires available providers in primary care provider groups and
load limits limits surgeon and and psychiatry licensing
programmer
Availability of third- +++ ++ + ++++ +++
party payment Precertification generally Limited coverage Very limited coverage Precertification required Precertification sometimes
required for managed plans for expensive agents required
Sources of practice Electrode placement; Motor threshold Dosing; surgical Selection of agent; dosing Therapy manuals exist,
variation affecting dosing; number of determination (dosing); complication rate but outcome is sensitive to
outcome treatments coil location; number of therapist skill
treatments
Caregiver Significant caregiver burden Self-transportation to None after implant Possible need for monitoring None
considerations related to transportation treatment of adherence; overdose
and monitoring potential
Abbreviations: CBT cognitive behaviour therapy, IPT interpersonal therapy, ECT, electroconvulsive therapy; MDD, major depressive disorder; TMS, transcranial magnetic stimulation; VNS, vagus nerve
stimulation.
pharmacotherapy has been the mainstay for treatment of major depression and a range of
comorbid conditions, including anxiety disorders and psychosis. Though limited to patients
with adequate insight, willingness, and ability to participate, evidence-based psychotherapies
are effective treatments for major depression (Thase et al., 1997) and also may ameliorate
comorbid conditions, as patients generally improve their state of mind or change maladap-
tive behavior. While all treatments appear to be affected to some extent by medication resis-
tance, the available evidence would support ECT and VNS in the most treatment-resistant
patients (Prudic et al., 1996; Rasmussen et al., 2007).
Effectiveness
The evidence in support of TMS efficacy in MDD comes from more than 30 random-
ized, controlled trials (RCTs) that were FDA approved in 2008 and based on results of an
industry-sponsored, large-sample (n = 301) RCT (O’Reardon et al., 2007), as well as inde-
pendent replication in an National Institutes of Health–sponsored, large-sample (n = 190)
RCT (George et al., 2010). These data show a rather modest remission rate for TMS, primar-
ily in patients who were younger, minimally treatment resistant, had a less chronic course of
depression, and were without psychosis.1
However, the data that are perhaps most comparable to the effectiveness of TMS in
the treatment of MDD in a typical private practice are the open-label data from the piv-
otal trials. Open-label data are arguably more comparable to those from a community
TRD clinic or private practice. The open-label crossover and 3-week continuation of the
industry-sponsored pivotal clinical trial were encouraging: the cumulative remission was
27.1% and response rates was 42.4% after 6 weeks of treatment and 36.5% and 45.9% after 9
weeks (Avery et al., 2008).
To the obvious interpretive caveats associated with open label treatment, it must be
added that the 9 week outcomes included the addition of antidepressant monotherapy
during the three weeks of taper. Many would argue, however, that data from the “real-world”
of clinical practice are essential in evaluating a treatment. Two recent post marketing studies
provide a glimpse into how TMS has performed in clinical practice. These open label stud-
ies differed from the controlled industry sponsored and NIH trials in a number of ways.
A broader range of patients were enrolled at the discretion of the treating clinician: those
with, bipolar depression, depression not otherwise specified, and those with variable sever-
ity and treatment resistance including previous ECT non-responders. These studies further-
more employed variable technique including right sided and bilateral stimulation, flexible
and therefore at times more intensive dosing, variable continuation and maintenance treat-
ments, and allowed for the use of concomitant antidepressant medications.
Connolly et al. published a retrospective review of the first 100 patients (85 acute
and 15 maintenance cases) treated at the University of Pennsylvania over three years fol-
lowing FDA approval in 2008. Patients receiving an index course of treatment were flex-
ibly dosed with up to 30 treatments over six weeks. A range of outcome assessments were
employed in the study, with primary outcome of the CGI-I at 6 weeks. Accordingly, the
1. A full discussion of the efficacy data can be found in Chapters 3 and 9.

CGI response rate in this study was 49.5%, HRDS response and remission rates were
42.5% and 40%.
Carpenter et al. reported on a study of 307 outpatients treated in 42 different clini-
cal TMS centers including 32 private practice, 7 academic and 3 non-academic institutions.
Patients were treated with open label left DLPFC stimulation according to standard proto-
col of up to six weeks of treatment 5 days a week, 3000 pulses per session. Outcomes were
assessed using clinician rated (CGI) and patient rated scales (PHQ-9, IDS-SR.) The authors
reported that categorical response and remission rates were consistent in clinical magnitude
on all outcome measures used in the study (CGI-S, PHQ-9, and IDS-SR). They note a
response rate of 58% as defined by CGI-S ≤ 3 “mildly ill or better” at the end of acute treat-
ment, with 37.1 achieving remission as defined by CGI-S of ≤ “borderline mentally ill: or
“normal not at all ill”. In contrast to the results from multisite sham-controlled trials, treat-
ment resistance was a less robust predictor of response and remission, as 54% of the patients
in the study population met criteria for resistance to more than one adequate antidepressant
medication trial during the current illness episode, and patients who had failed a minimum
of one adequate antidepressant trial were as likely to be TMS responders as those who had
failed two or more trials in the current episode.
Figure 5.1 shows effect sizes for TMS versus antidepressants and ECT, comparing
results from the pivotal trial versus recent metaanalyses. In this context, TMS demonstrates
favorable efficacy compared with ADMs, especially for the labeled indication of treatment
resistance, but fails to measure up to the more robust effect size for ECT.
In an open-label setting, the Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) trial demonstrated that depressed patients unremitted after two antidepres-
sant trials are increasingly unlikely to respond to subsequent medications (Rush et al.,
1
0.91
0.9
0.83
0.8
0.7
0.6 0.55
0.5 0.49
0.44
0.4
0.31
0.3
0.2
0.1
0
m MS
on ure
ilu M
T
M
EC
Fa AD
e
ly
re
AD
AD
sa ll T
il
pl
Fa
2
ra
≥
ve
AD
O
FIGURE 5.1 Comparative Effect Sizes of TMS (Transcranial Magnetic Stimulation), ADMs (Anti-Depressant
Medication) and ECT (Electroconvulsive Therapy) on the HAM-D scale (Hamilton Depression Rating Scale).
2006). Specifically, in STAR*D, crossover to a different ADM yielded remission rates of 21%

after one failed trial, 16% after two failed trials, and only 6.9% after three failed trails. Data
from the open label extension of the TMS pivotal trial show that TMS treatment compares
favorably with ADMs, with 25.6% remitting after one failed ADM trial in the present epi-
sode and 17.9% and 18.2% after two and three failures, respectively (Avery et al., 2008).
Results for psychotherapy are similar to those for TMS and ADM for patients who
failed one antidepressant trial. In the STAR*D trial, patients unresponsive to citalopram
discontinued this medication and switched to 16 cognitive behavior therapy sessions over
12 weeks (N = 36); sessions in stage 2 showed a remission rate of 25% (Thase et al., 2007).
A recent comparative effectiveness review by the Agency for Healthcare Research and
Quality on Nonpharmacologic Treatments for Major Depression did not identify eligible
studies gauging the effect of psychotherapy in patients with higher levels of treatment resis-
tance (Gaynes et al., 2011).
TMS versus ECT
How does the efficacy of TMS in MDD compare to that of ECT? Surprisingly, the majority
of head-to-head studies have failed to demonstrate a statistical advantage for either treat-
ment (Figure 5.2). However, most of the studies have generally been too small to determine
noninferiority or equivalence. The exception thus far was a randomized trial of 46 depressed
patients treated alternately with TMS (15 treatments left dorsolateral prefrontal cortex
(DLPFC) totaling 15,000 pulses, 110% of motor threshold) versus titrated ECT (82% bilat-
eral 1.5X threshold/18% unilateral 2.5X threshold, flexibly dosed [mean 6.3 treatments];
80
70
60
50
ECT
40 TMS
30
20
10
0
Grunhaus, Pridmore, Janicak, Grunhaus, Rosa, Schulze- Eranti,
2000 2000 2002 2003 2006 Rauch, 2007
(n = 21) (n = 32) (n = 22) (n = 40) (n = 35) 2005 (n = 46)
(n = 30)
F I GUR E 5.2 TMS
versus ECT efficacy outcomes in depression without psychotic features. Reprinted
from Avery (2008).
Eranti et al., 2007). Ham-D scores at the end of treatment were significantly lower in the
ECT group, and the number of remitted patients also favored ECT (13/22; 68.4%) over
TMS (4/24; 16.7%).
Practical Considerations
Patients and caregivers invariably want to understand the treatment plan. What constitutes
an adequate trial? Of the treatments listed in Table 5.3, ECT has the most rapid onset of
treatment response, followed by TMS, pharmacotherapy, psychotherapy, and VNS. This
same order applies to the duration of an effective treatment course. For ECT, this is on the
order of 6–12 treatments given over a 2- to 5-week period, followed by TMS and pharma-
cotherapy with daily treatments or doses given over a 4- to 6-week period. Although it is
difficult in practice to find therapists trained to provide the manual-driven, evidence-based
psychotherapies that range from 12 to 16 sessions, most treatments are offered at weekly
intervals and require at least that many weeks to achieve an outcome. Finally, those indi-
viduals who have received a VNS implant need to understand that improvements develop
slowly over many months and require gradual titration of the stimulus parameters to pro-
mote tolerability.
Two things are generally required for a treatment to be widely available, presuming an
adequate demand already exists: trained providers who have access to the technology and
mechanisms for reimbursement; both predict whether the treatment is available to meet
demand. Currently data are limited on the number of neurostimulation practitioners in the
United States. With FDA approval of the TMS device and the fact that it can be admin-
istered in an office setting, the number of practices offering TMS appears to be growing
steadily.
The second predictor, availability of reimbursement, continues to affect the growth of
TMS, although the number of insurers that reimburse for TMS services is increasing. This
is very different from reimbursement for VNS. Although VNS has an FDA indication for
the treatment of MDD, the Centers for Medicare and Medicaid Services and other private
insurers have denied coverage for VNS for the treatment of MDD in contrast to the coverage
for epilepsy (McCall & Rosenquist, 2007).
Predicting and Influencing the Outcome

of TMS Treatment
Patient-related Factors
As discussed earlier, the strongest predictor of efficacy to date appears to be the level of treat-
ment resistance in the TRD patient, with fewer prior antidepressant treatment failures in the
present illness associated with better outcomes (Lisanby et al., 2009). In other studies, posi-
tive predictors have included a shorter duration of the present illness, younger age, greater
baseline sleep disturbance, and lack of comorbid anxiety or psychosis (Eranti et al., 2007;
Lisanby et al., 2009; Aguirre et al., 2011; Brakemeier et al., 2007).
What about patients with bipolar disorder? Limited data suggest that patients with
bipolar depression respond somewhat less robustly than those with unipolar depression.
Twenty of the 100 patients in the Connolly et al., 2012 effectiveness study who were treated
with TMS had bipolar disorder (11 bipolar I, 4 bipolar II, and 5 bipolar not otherwise speci-
fied). A subgroup analysis showed that the 6-week Clinical Global Impression-Improvement
scale (Guy, 1976) response and remission rates for patients with bipolar depression was 35%
and 15%, respectively, compared with 50.6% and 24.7% for the overall sample.
Results of TMS treatment of mania are mixed. An early blinded, controlled trial
demonstrated significant improvements in mood for patients treated with right, rather
than left, prefrontal TMS at 20 Hz (Grisaru, Chudakov, Yaroslavsky, & Belmaker, 1998).
A subsequent open-label study using right high-frequency prefrontal TMS in the treat-
ment of bipolar mania found that TMS was associated with a reduction in manic symptoms
(Michael & Erfurth, 2004). However, Kaptsan et al. (2003) could not replicate this result
in a sham-controlled study. Reports of TMS triggering cycle into the manic state are rare
(Dolberg, Schreiber, & Grunhaus, 2001). Li et al. (2004) reported that three of seven bipolar
depressed acute responders to TMS were successfully maintained without relapse for 1 year
with weekly maintenance treatment. However, there are no studies specifically examining the
long-term management of bipolar disorder or those with rapid cycling type.
Post-stroke depression presents a unique challenge in terms of efficacy and safety
because of the elevated risk for seizure following cerebrovascular accident (Burn et al., 1997).
TMS has been used widely, safely, and successfully in post-stroke rehabilitation. Both low
(contralateral)– and high (ipsilateral)–frequency TMS stimulation of motor cortex appear
to be of benefit in the treatment of motor dysfunction and disability in patients with isch-
emic stroke (Emara et al., 2010). A small study of treatment-resistant post-stroke depression
(N = 20) demonstrated efficacy for 10 sessions of active (10 Hz, 110% of motor threshold)
versus sham stimulation of left DLPFC ( Jorge et al., 2004). Reduction in depressive symp-
toms in this study was not influenced by patient age, type or location of ischemic stroke,
volume of left frontal leukoaraiosis, or distance from coil to cortex; however, it did correlate
positively with greater frontal gray and white matter volumes. Similarly, 15 sessions of left
DLPFC TMS (10 Hz; 110% of motor threshold) was effective compared with sham stimu-
lation in a group of elderly patients (N = 92) with vascular depression; again, frontal gray
matter volume was a positive predictor ( Jorge, Moser, Acion, & Robinson, 2008). In both
studies, adverse effects were mild and consistent with other depressed populations.
Treatment-related Factors
A number of treatment-related factors may affect the antidepressant response to TMS. These
include stimulation intensity, frequency, number of pulses administered, and duration of
the treatment course (Gershon, Dannon, & Grunhaus, 2003; Padberg et al., 2002; Sachdev
et al., 2002). Over time, TMS studies have used steadily higher intensity stimuli relative to
motor threshold and extended the number of stimulations per session, as well as the dura-
tion of the treatment course. These modifications appear to improve the efficacy of the treat-
ment (Gershon et al., 2003). Concerns regarding the potential for inducing seizures through
excessive stimulation have largely been addressed with the safety screening, which excludes
high-risk individuals (Keel, Smith, & Wassermann, 2001), and the inclusion of adequate
intertrain interval between pulse trains.
One study examined the safety, tolerability, and effectiveness of a reduced intertrain
interval, thereby increasing the number of stimulations per treatment session (10 Hz,
5-second pulse train with 10-second intertrain interval, 120 trains per session for a total
of 6800 pulses over 34-minute session and 34,000 pulses weekly; Hadley et al., 2011). In
open-label treatment, these higher doses were well tolerated by the 21 patients treated, with
no seizures or serious adverse events recorded. Twelve patients achieved remission with a
Beck Depression Inventory score of 10 or lower, with a mean of 15.3 (14.2 standard devia-
tion) sessions (range 3–45 sessions), and six patients showed remission after 1 week (five
sessions). If these results are representative, it appears that a more aggressive approach to
treatment may produce a more robust and rapid response.
Coil Type and Placement

Based on the manner of construction of the electromagnet, there are four coil types that
have been engineered for research and treatment purposes. These include the circular coil,
the figure-8, the C-shaped coil, and, most recently, the so-called H or deep coil (Brainsway),
recently approved by the FDA for use in the treatment of depression. At the time of this writ-
ing, at least four manufacturers produce TMS devices, while only two (Neurostar, Malvern PA,
USA and Brainsway, Jerusalem, Israel) have received FDA approval for depression. Some man-
ufacturers market a range of products depending upon the intended use. For high-frequency
TMS, a cooling system is required to prevent overheating of the electromagnet with repeated
stimulation. While the neurophysiological responses to TMS vary according to coil and stimu-
lator type, waveform shape and polarity, coil position, and orientation relative to target cortex
(Davey, Epstein, George, & Bohning, 2003; Kammer, Beck, Erb, & Grodd, 2001; Kammer,
Beck, Thielscher, Laubis-Herrmann, & Topka, 2001; Thielscher & Kammer, 2004), currently
there are no clinical trials that directly compare the type of coil or the manufacturer.
Magnetic field strength decreases rapidly with distance from the coil (Dolberg,
Schreiber, & Grunhaus, 2001). Therefore, increasing the distance from the coil to the target
cortex decreases the intensity of the stimulation reaching the brain, which is in turn nega-
tively correlated with the degree of stimulation-induced brain activation and antidepressant
response (Kozel et al., 2000; Mosimann et al., 2002; Nahas et al., 2001). The reduced efficacy
seen in the elderly may be due in part to age-related atrophy, leading to an increased distance
between the coil and cortex (Mosimann et al., 2002, 2004; Hadley et al., 2011; Manes et al.,
2001; Fregni et al., 2006). Nahas et al. (2004) tested these ideas by adjusting the TMS dosage
by the distance to prefrontal cortex in a group of older adults. This resulted in a higher rate
of responders than in earlier studies, suggesting that one might increase dosage intensity to
compensate in elderly patients. Further research is required to determine whether specific
coil types designed for deep stimulation would similarly improve outcomes in the elderly.
Safety and Management of Adverse Effects

Arguably, the main advantage of TMS is its lack of systemic side effects, compared with more
invasive treatments. However, the potential for TMS to induce a seizure requires careful attention
to patient selection and preparedness for this eventuality. In a recent review focusing on seizure
risk, the authors concluded that the risk of seizures is low, with some caveats (Loo, Mcfarquhar,
& Mitchell, 2008). Most cases of accidental seizures have occurred in patients with preexisting
neurological disorder; however, they may also occur in the absence of predisposing factors at high
stimulation intensities. The transcranial magnetic stimulation adult safety screen (TASS) is a useful
instrument for identifying individuals who might be at greater risk for seizure and other adverse
effects of TMS (Keel et al., 2001). The TASS includes questions about predisposing neurological
history, such as head injury, epilepsy or family history of seizure, medications, and neurosurgical
procedures, and also screens for the presence of ferrometallic implants (within 30 cm of the treat-
ment coil), which is arguably the only absolute contraindication for TMS treatment. Other, rela-
tive contraindications include heart disease, cardiac pacemakers, and medication pumps.
Bae et al. (2007) reviewed 30 publications that described the use of TMS in 280 patients
with epilepsy and found four instances of seizures occurring during treatment (crude risk, 1.4%).
In most instances, the seizure was similar to the patient’s typical seizure, and no instances of
status epilepticus or life-threatening seizures were reported. Thirteen studies have reported sei-
zure frequencies before and after TMS. Overall, it appears that TMS may actually reduce seizure
frequency for a period of 2 to 8 weeks following treatment (Bae et al., 2007). TMS has been
successfully reintroduced without recurrence to a patient with no known risk factors who expe-
rienced a seizure after the fourth treatment with the addition of valproate (Bagati et al., 2012).
Nevertheless, the TMS treatment suite should have trained and vigilant staff and all
necessary equipment available to manage the patient who experiences a seizure during the
course of treatment. A licensed health professional should be in the treatment room at all
times during the delivery of a treatment, and a responsible physician should be close enough
to the treatment area to respond immediately should there be an emergency.
Figure 5.3 lists equipment and measures to take should a seizure occur, which include
immediately stopping TMS treatment and basic airway and cardiovascular management and
Equipment Needed
Sphygmomanometer
Stethoscope
Treatment of Seizures
1. General measures
• Stop the TMS
• Maintain a clear airway by turning the patient on one side, with head low to encourage gravity
drainage of secretions and vomitus and to prevent aspiration.
• Position the patient so as to prevent injury by falling or knocking into objects.
• Do not try to pry clenched jaws apart to place an object between teeth.
• Observe and be able to describe the duration and focal elements of the seizure.
• Monitor respirations, blood pressure, and pulse.
2. Considerations for Consultation-Referral

Consult with a neurologist on all seizures before continuing TMS therapy (Rosedale, M: ISEN
Certificate Course 2009)
FIGURE 5.3 Safety Measures In the TMS Treatment Room

monitoring. If the treatment facility lacks access to a code paging system, licensed person-
nel with basic a cardiac life support training should be available to manage the patient until
emergency technicians arrive.
High-frequency TMS is associated with intensity-related discomfort at the site of
stimulation, presumably related to direct stimulation of the superficial nerves in the scalp.
Methods to diminish this include minor repositioning of the coil, use of topical lidocaine,
and specialized shields that are placed over the surface of the treatment coil to attenuate
the magnetic field where it makes contact with the scalp (Borckardt et al., 2008). TMS
may also produce more lasting headache and scalp soreness, which are generally treated
with analgesics. Treatment dropout is rare, but some individuals may require a diminished
intensity of stimulation, at least initially, in order to build up tolerance for the unpleas-
ant sensation. Headache and application-site pain declines over the course of treatment
as patients become tolerant ( Janicak et al., 2008), and this may help to reassure patients
who experience these adverse effects. Patients and staff in the treatment room must wear
earplugs with 30-dB protection to prevent auditory damage from the loud clicks associ-
ated with each TMS pulse.
Of note, TMS does not appear to have a direct effect on sleep, that is, it produces nei-
ther sedation nor activation, as may be seen with some ADMs (Rosenquist, Krystal, Heart,
Demitrack, & Vaughn McCall, 2012). Instead, sleep improves as depression improves gener-
ally. For this reason, the TMS practitioner may need to consider a hypnotic for those patients
with this problem, at least early in the course of treatment.
Conclusions
TMS appears to have gained a place in the treatment of major depression and compares
favorably with other treatment alternatives for patients with a moderate degree of treatment
resistance or where there are concerns about the ability of the patient to tolerate general
anesthetic or drug side effects. The reimbursement environment for TMS may be improving
over time, with local coverage decisions having been realized in some Medicare jurisdic-
tions. There is an ample and expanding literature describing techniques of administration
and continued technological development in the field that may ultimately lead to better
outcomes.
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6
Practical Administration
of Transcranial Magnetic
Stimulation in a Clinical Setting
Daniel F. Maixner
Introduction
This chapter focuses on the practical aspects of providing transcranial magnetic stimulation
(TMS) in the clinical setting. Prior to establishing a clinical TMS program, practitioners need
to understand a host of issues. These include space and facility requirements and equipment
used in performing TMS. Also, because TMS is often done in collaboration with nurses or
medical assistants, personnel and training issues are covered. How patients are selected, evalu-
ated, and managed for TMS is reviewed, and patient education and the consent process are
explained. Consistency for any team of clinicians performing a procedure is important in
order to provide safe and effective care for patients and to enhance outcomes. To facilitate this
consistency and TMS program development, TMS policy and standard operating procedure
topics are discussed. Finally, billing and reimbursement issues are identified and reviewed.
Space, Facilities, and Equipment

Treatment Room and Basic Equipment
Adequate space is needed for equipment and staff who provide TMS. In the treatment room,
enough space should be allowed for the TMS device, a comfortable chair for the patient,
and workspace for the treater (typically a desk, work computer, and chair). Storage space for
supplies and TMS device–related items, patient charts, and other work items is important.
The size of the room is not standard; one manufacturer suggests a room size of 12′ × 15′ for
their device, which includes an electrical reclining chair and computer console (Neuronetics
I, 2012). A dedicated electrical outlet should be available.
In the room where TMS is performed, sound may be an issue. The TMS coil can pro-
duce loud intermittent clicking. The walls of the treatment room provide an adequate sound
barrier so as not to disturb other activities in the building. Extra insulation or thicker doors
could be considered. Also, due to the intense intermittent sound of the device, a supply of
foam hearing protection for both the treater and patient should be available (Rossi, Hallett,
Rossini, & Pascual-Leone, 2009).
Medical crises with TMS are rare. The most serious known complication of TMS
is seizure during a treatment session (Rossi et al., 2009). This emergency necessitates that
the TMS program clinicians be aware of what equipment is required by their local facility
administrators and policies. At a minimum, the treater should have ready access to a tele-
phone in the room to call for immediate help and alert emergency medical services (EMS).
Other equipment that is not mandatory but is useful for managing a seizure and maintain
airway include an ambu bag or wall suction.
TMS Devices
A number of TMS devices are produced by various manufacturers. These devices vary in the
shape of coil used, but most use focal stimulation of the superficial cortex to either activate
or inhibit neuronal function. Other forms of transcranial magnetic stimulation technology
are emerging. A newer type of “deep” TMS device may soon be commercially available. It
uses a different coil shape and technology to stimulate deeper brain structures more glob-
ally (Rosenberg, Shoenfeld, Zangen, Kotler, & Dannon, 2010). Another device made by
Neosync, Inc. (Waltham, MA) uses a form of “synchronized” TMS to target the brain’s natu-
ral alpha electroencephalographic (EEG) rhythm; it is currently undergoing investigational
study for depression (Clinicaltrials.gov, 2013).
Only two devices are US Food and Drug Administration (FDA) approved for major
depression. The Neurostar system by Neuronetics, Inc. (Malvern, PA) was the first TMS
device to be approved specifically for the treatment of major depression in 2008. More
recently, the novel design of the Brainsway, Inc. ( Jerusalem, Israel) deep TMS device was
approved in 2013 using the FDA 510(k) mechanism of showing substantial equivalence
in efficacy and safety to the Neuronetics, Inc. (Malvern, PA) device (Brainsway, 2013).
MagVenture, Inc. (Atlanta, GA) and Magstim, Inc. (Whitland, United Kingdom) both
produce TMS devices that are FDA approved for use in diagnostic testing, such as periph-
eral nerve stimulation/evoked potential tests, but do not carry an indication specifically
for depression (MagVenture, 2012; Magstim, 2012). Nonetheless, some clinics use these
devices for therapeutic purposes.
Factors that influence the choice of a device for use in the clinical setting include cost,
equipment included with the system, and ease of use. For example, the Neurostar system
comes with an electric reclining chair for comfort, a patient record computer system, the
TMS device, and a touch screen console to manipulate settings. However, added costs are
required for disposal sensors that ensure good coil contact with the scalp and mitigate sur-
face sensations or pain from the stimulation. As newer TMS technologies become available,
clinicians need to learn more about the pros and cons of each device in terms of safety and
tolerability, efficacy, and space/facility requirements.
P r ac t i ca l A d m i n i s t r at i o n of T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n | 71
Personnel and Training

As a medical procedure, it is recommended that a licensed physician prescribe TMS. Properly
trained non-physician personnel can administer TMS under the direction of the physician
prescriber (Rossi et al., 2009). Commonly, the treater is a registered nurse, but some clinics
use qualified medical assistants who are well supervised and trained. During the daily treat-
ment sessions, the physician does not need to be present in the treatment room. However,
due to the possibility of tolerability issues, medical emergencies such as a seizure, and even
psychiatric emergencies, the physician should be in close proximity to the treatment room,
either in the same building or on the same floor.
When initiating a course of TMS, a physician typically completes the motor threshold
procedure at the first session. Training should be extensive enough to establish proficiency
in mapping the motor cortex, identifying the target muscle movement, and determining the
motor threshold level. The physician should be aware of dosing strategies and safety risks
associated with various device parameter options. Specifically, clinicians must be aware of
the risks with increased intensity, frequency, and shorter decreased intertrain intervals of the
TMS stimulus, such as pain, facial muscle contractions, and elevated risk of seizure.
Team members who provide the treatments also need adequate training that includes
use of the TMS device and placement of the coil at the target treatment site. Understanding
how to optimize patient comfort is important as well. During each session, the patient is
monitored directly in the treatment room. The patient must be observed for any abnormal
reactions that could indicate dangerous side effects, such as abnormal motor activity, which
could place the patient at risk of developing a seizure. TMS team members should be knowl-
edgeable about what questions to ask patients upon arrival that may affect seizure threshold,
such as medication changes, decreased sleep, and increased caffeine use. Changes should be
communicated to the physician lead. In the event of a seizure, treatment nurses or assistants
need to fully understand what the protocol is for managing this complication and how and
when to call for emergency services and help.
Currently there are no credentialing programs for physicians and team members who
administer TMS. Many attend educational training courses and workshops to enhance their
knowledge about TMS. The International Society for ECT and Neurostimulation offers
this type of course (Neurostimulation, 2013). Alternatively, well-established device manu-
facturers provide training programs. Regardless of the training strategy used, TMS program
medical directors and administrators need to develop procedures for training team members
and establish the frequency of training. Privileging to conduct TMS may also require special
approval from local hospital or clinic administrators.
Patient Evaluation, Selection, and Monitoring

Prior to prescribing TMS, clinicians should complete a thorough assessment of the patient to
ensure that a treatable condition likely to respond to TMS is present. Generally, TMS is only
FDA approved for depression. The implications of using TMS off label are discussed below
in the reimbursement section of this chapter. In addition to the psychiatric assessment of
the patient, the pre-TMS consultation should include a review of medical problems, with an
emphasis on conditions that may put patients at greater risk with TMS. As with any assess-
ment, physicians should look for medical and neurological comorbidities that may mimic
the condition being considered for treatment. Findings from this evaluation may lead the
clinician to obtain a more complete physical exam/neurological exam, laboratory tests, or
neuroimaging. Because TMS is not associated with cognitive side effects and may actually
positively affect cognition (Guse, Falkai, & Wobrock, 2010), pretreatment neuropsychologi-
cal tests are not necessary. Currently there are no required pre-TMS exams or tests, and per-
formance of any laboratory tests should be driven by a clinical indication or concern.
A simple screening tool proposed by Keel et al. (2001) can be used to screen for a number
of possible issues prior to the start of TMS (Figure 6.1). If questions are answered with a yes, then
further exploration is warranted, but may not necessarily preclude a patient from receiving TMS
(Keel et al., 2001). These screening questions focus on neurological conditions, risk of metal or
medical implants, and medications that could impact safe delivery of TMS and increase risks.
The acute TMS course often consists of Monday through Friday daily TMS sessions for
4–6 weeks. A plan should be designed for how patients will be monitored during this critical
time. An assessment every 1–2 weeks is reasonable. In treating depression, rating scales, whether
clinician rated or patient rated, can be helpful in measuring outcome. Regular visits during the
TMS course also allow the TMS team to evaluate tolerability issues and changes in medical status
or medications. Information gathered from the assessments informs the team whether a repeat
motor threshold procedure is necessary or changes in dosing of the TMS may be beneficial.
Patient Education and Consent

Patients should be given clear information to ensure they understand the risks and benefits
of the TMS procedure. Commonly, general patient education information is presented in a
1. Have you ever had an adverse reaction to TMS?
2. Have you ever had a seizure?
3. Have you ever had a stroke?
4. Have you ever had a head injury or neurosurgery?
5. Do you have metal in your head (outside of your mouth) such as shrapnel, surgical clips, or
fragments from metalwork?
6. Do you have any implanted devices such as cardiac pacemakers, medical pumps, or intracardiac
lines?
7. Do you suffer from frequent or severe headaches?
8. Do you have any other brain-related condition?
9. Have you had any illness that caused brain injury or damage?
10. Are you taking any medications

11. For women of childbearing age: Are you sexually active? If so, are you not using reliable birth
control?
12. Does anyone in your family have epilepsy
FIGURE 6.1 TMS Adult Safety Screen Questions.

If you answer yes to any questions, further exploration by a TMS physician should be done.
Source: Keel, 2000.
pamphlet or in web page materials to facilitate discussion. If both clinician and patient agree
to pursue TMS as a therapeutic modality, a detailed consent form should be reviewed and
signed. Figure 6.2 provides a consent form sample that can be adapted to meet your needs.
This is a patient consent for a medical procedure called Transcranial Magnetic Stimulation (TMS).
This consent form outlines the treatment that your doctor has prescribed for you, the risks of this
treatment, the potential benefits of this treatment to you, and any alternative treatments that are
available for you if you decide not to be treated with TMS.
Be sure to ask your doctor any questions that you may have about TMS.
Dr. has told me that I have the following condition:
The doctor has explained to me that:
A. TMS is a medical procedure. A TMS treatment session is conducted using a device called a
“treatment coil” or magnet that delivers pulsed magnetic fields. These magnetic fields are a similar
type and strength as those used in magnetic resonance imaging (MRI) machines.
B. TMS is a safe and effective treatment for patients with depression.
C. Specifically, TMS has been shown to relieve depression symptoms in adult patients who have
been treated with one antidepressant medication given at a high enough dose and for a long enough
period of time but did not get better.
D. At this time, the US Food and Drug Administration-approved indication for TMS does not include
patients who did not get better after taking two or more antidepressant medications at a high enough
dose and for a long enough period of time or who did not take any antidepressants during this
current period of depression.
E. During a TMS treatment session, the doctor or a qualified member of the clinic staff will place
the magnetic coil gently against my scalp on the front region of my head. The magnetic fields that
are produced by the magnetic coil are pointed at a region of the brain that scientists think may be
involved with depression.
F. To administer the treatment, the doctor or a qualified member of the clinic staff will first position
my head in the head support system. At the first session, a procedure will be done to establish the
appropriate stimulation dose. The magnetic coil will be placed on the side of my head, and I will hear
a clicking sound and feel a sensation on my scalp. The doctor will then adjust the TMS coil so that the
device will give just enough energy to send electromagnetic pulses into the brain so that my hand
twitches. The amount of energy required to make my hand twitch is called the “motor threshold.”
Everyone has a different motor threshold, and the treatments are given at an energy level that is
related to my individual motor threshold. The motor threshold procedure takes about 20–30 minutes,
and my doctor will determine how often it is reevaluated or repeated.
G. Once the motor threshold is determined, the magnetic coil will be moved, and I will receive the
treatment as a series of “pulses” lasting commonly around 5 seconds with a “rest” period of about
15–30 seconds between each pulse series. Treatment is to the front side of my head and will take
about 40 minutes. I understand that this treatment does not involve any anesthesia or sedation and
that I will remain awake and alert during the treatment. I will receive these treatments 5 times a week
for 4–6 weeks (20–30 treatments). My doctor will evaluate me at least weekly during this treatment
course. The treatment is designed to relieve my current symptoms of depression. The doctor may
modify these treatment parameters, such as adding additional treatments or stimulating a different
place on my head or the other side of my head.
H. During the treatment, I may experience tapping or painful sensations at the treatment site while
the magnetic coil is turned on. These types of sensations were reported by about one-third of the
patients who participated in the research studies. I may also experience muscle contractions around
the site of stimulation, and these may be painful. I may also experience tooth pain with stimulation.
I understand that I should inform the doctor or his/her staff if the sensation is painful. The doctor
may then adjust the dose or make changes to the location where the coil is placed in order to help
make the procedure more comfortable for me. I also understand that headaches were reported in half
of the patients who participated in a recent clinical trial for a TMS device. I understand that both the
discomfort and headaches got better over time in the research studies and that I may take common
over-the-counter pain medications if a headache occurs.
FIGURE 6.2 Consent for Transcranial Magnetic Stimulation

I. The following risks are also involved with this treatment:

TMS should not be administered to anyone who has magnetic-sensitive metal in their head or
magnetic-sensitive metal within 12 inches of the TMS coil that cannot be removed. Failure to follow
this restriction could result in serious injury or death. Objects that may have this kind of metal
include:
• Aneurysm clips or coils

• Carotid or cerebral stents
• Implanted stimulators
• Electrodes to monitor brain activity
• Ferromagnetic implants in ears or eyes
• Bullet or shrapnel fragments
• Other metal devices or objects implanted in the head
• Pellets, bullets, or metallic fragments less than 12 inches from coil
• Magnetically activated dental implants
• Facial tattoos with metallic ink
J. There is no guarantee that this treatment will improve my condition, as TMS is not effective for
all patients with depression. Any signs or symptoms of worsening depression or unusual behavior or
thoughts should be reported immediately to your doctor. You may want to ask a family member or
caregiver to monitor your symptoms to help you spot any signs of worsening depression or unusual
behavior.
K. Seizures (sometimes called convulsions or fits) have been reported with the use of TMS devices.
In a recent large multicenter clinical trial, however, no seizures were observed with use of TMS for
approximately 300 patients, although seizures have been reported in clinical practice with TMS.
Although the risk of having a seizure is quite low, complete medical information must be provided to
your doctor so that your level of risk can be assessed and discussed with you.
L. Because TMS produces a loud click with each magnetic pulse, I understand that I must wear
earplugs or similar hearing protection devices with a rating of 30 decibels or higher of noise
reduction during treatment.
M. I understand that most patients who benefit from TMS experience results by the sixth week of
treatment. Some patients may experience results in less time, while others may take longer.
N. I understand that I may discontinue treatment at any time.

O. Other options for your condition could include: ______________________________.
I have read the information contained in this consent form about TMS and its potential risks. I have
discussed it with Dr. ________________ who has answered all of my questions. I understand there are
other treatment options for my depression available to me, including medications, psychotherapy,
and other brain stimulation treatments such as electroconvulsive therapy. These alternative treatment
options were discussed with me.
I, therefore permit, Dr. ____________________ and his/her staff to administer this treatment to me.
_____________________________ ____________________________________ _________________
Patient’s Printed Name Patient’s Signature Date
_____________________________ _____________________________________ __________________
Legal Representative’s Printed Name* Legal Representative’s Signature Date
*If signing as the legal representative, I represent to the __________________ that I am the legal
representative of the patient and agree to provide proof of legal representation, if requested. Should
my legal authority terminate, I agree to provide written notification to the ___________.
Clinician’s Signature: ___________________________________________ Date: _____________
FIGURE 6.2 (Continued)
Items covered in the consent form include who the prescribing doctor is and the condi
tion being treated. The consent details how the target location is obtained during the motor
threshold procedure, what to expect during this session, and how long this first session will
last. Patients are educated that after a motor threshold is established, a brain region is tar-
geted and the treatment coil is placed.
Patients are given information about the duration of each TMS treatment and how they
may experience the stimulation, for example, “you will feel a tapping sensation on your scalp for
5 seconds followed by a pause for 25 seconds. This cycle will continue for about 40 minutes.”
A review of the number of anticipated TMS sessions for a treatment course is discussed.
Potential side effects such as scalp pain, headache, and muscle/facial twitching are
noted. Reviewing the risks of having any magnetic-sensitive metal in or around the head
should be highlighted. With seizure risk being very low, yet still the most severe potential
adverse event, a special section about this risk should be listed. During the procedure, a loud
clicking sound occurs, and patients should be expected and instructed to use ear protection.
Finally, patients are educated to report mood changes, including worsening of mood.
Policies and Standard Operating Procedures

A policy may be defined as a high-level overall plan of acceptable procedures and strategies.
Standard operating procedures (SOPs) are detailed written instructions that help ensure uni-
formity in the performance of a plan or procedure. Often, hospitals, administrative depart-
ments, or facilities require at least general policies and guidelines in conducting a procedure
such as TMS. However, SOPs can be further developed to enhance consistency for all team
members in the administration of TMS treatments. These SOPs can operationalize strategies
to assist in compliance with regulations, improve safety, and increase better outcomes. Both
policies and SOPs can be developed simultaneously and often complement each other.
Definitions and standards are outlined in a policy. The TMS procedure is generally
defined and explained, including how the motor threshold is defined and what generally
consists of the typical course of treatments. Standards that the TMS program will adhere
to are established and may include who conducts the motor threshold procedure and treat-
ments, general patient selection, consent process, and the fact that team members are appro-
priately trained. Finally, policies may also include a general description of items relevant to
patient clinical management and the type of documentation performed.
SOPs can be further designed to provide more details on how TMS is delivered and the
roles and responsibilities of each team member. One strategy for keeping both policies and
SOPs together for quick referencing is to create a manual or binder for all documents. Copies
of the manual can be made readily available to the team in various locations or offices. The
manual can be divided into many sections (Figure 6.3). The first section would include the
general policy document available for review. A section for TMS documents would include
medical chart templates (motor threshold procedure and daily treatment notes), ratings
scales, and any other assessment tools implemented by the team. The patient education mate-
rials section would include items shared with patients and families, such as TMS pamphlets
and a copy of the TMS consent form.
1. Policy document

2. Documents (note templates, rating scales, assessment tools)
3. Patient education materials (pamphlets and consent form)
4. Privileging and training of physicians and team members
5. TMS procedure details
a. Motor threshold
b. Coil placement
c. Dosing strategies
d. Nurse/medical assistant daily tasks
6. Clinical management
a. Evaluation process
b. Patient follow-up
c. Side-effect management (pain, seizure protocol)
7. Manufacturer information (contact information, device maintenance, supplies)
8. Important TMS research literature
FIGURE 6.3 Sections for a TMS Program Manual
The privileging and training section highlights how all team members are approved
to engage in the clinical tasks assigned to them and who is responsible for the privileging
approval. The privileging procedure may specify how long privileges are permitted or how
often renewal is required. For physicians, proficiency in the motor threshold procedure may
need to be demonstrated on regular intervals, and details of retraining for those clinicians
who become inactive in their skills can be outlined. Nurses or medical assistants who provide
the daily treatments should be trained to be proficient in use of the TMS device, coil place-
ment, and monitoring of tolerability issues with TMS and should demonstrate an under-
standing of seizure protocols. Training and privileging requirements vary from site to site,
and these procedures may need to be developed and reviewed with local administrators.
To provide consistency for the motor threshold procedure and duties of the team mem-
bers conducting the daily treatments, a TMS procedure section should be developed. In this
section, specific procedures of how the motor threshold is obtained are detailed for all phy-
sicians. The motor threshold is done at the start of the TMS course to establish a dosing
strategy and target site. The threshold appears to not change much over time (Zarkowski,
Navarro, Pavlicova, George, & Avery, 2009); however, outlining when a repeat threshold is
considered can be detailed. Reasons for redoing a motor threshold include dose tolerability,
pain at the treatment site, and changes in medication that potentially could alter threshold.
In addition, the coil placement strategy used to target the treatment site and approximate
the left dorsolateral prefrontal cortex (DLPFC) should be outlined. In the TMS pivotal trial
for depression, this placement was 5 cm anterior from the motor threshold spot (O’Reardon
et al., 2007). Data support that this “5-cm rule” may not be optimal and that the actual
treatment target site may be better estimated by a coil placement more anterior (Herbsman
et al., 2009). Today, current recommendations are for the coil to be placed 5.5–6 cm anterior
from the motor threshold location. Other strategies of targeting the left DLPFC are available
including use of the F3 EEG location (Beam, Borckardt, Reeves, & George, 2009) or neuro-
imaging strategies (Fitzgerald et al., 2009).
For daily treatments, a dosing strategy needs to be selected. Currently, the most
common strategy is to start with device settings that reflect similar parameters used in FDA
approval studies. Specifically, the starting point tends to be stimulation of the left DLPFC
at 120% motor threshold at a frequency of 10 Hz for 3000 pulses per session (O’Reardon
et al., 2007). However, over time, other dosing strategies that are based on new research
findings will emerge as alternatives. These strategies include increasing the number of pulses
to 5000-6000 per session (George & Post, 2011), using right-sided low-frequency (1 Hz)
stimulation (Fitzgerald et al., 2009), or combining low-frequency right-sided TMS with
high-frequency left-sided TMS (McDonald et al., 2006). More research on these dosing
strategies is needed in order to better evaluate outcomes (George, 2010). If a physician uses
a dosing strategy that is different from what is approved by the FDA or that targets a differ-
ent brain region, patients should be apprised of any potential added risks. Details of how
any alternate strategy is used should be described in the SOPs and may be justified on clini-
cal judgment of tolerability, patient symptoms, level of improvement, and advancements
supported in the research literature that shift standards of care. Daily tasks of nurses or
assistants can also be outlined and include how patients are greeted and assessed, treatment
room preparation, removal of jewelry or metal from around the head, use of hearing protec-
tion, patient positioning for comfort, coil placement and coil repositioning for stimulation
discomfort, end of session assessments for side effects, discharge to home instructions, and
medical record charting duties. Based on the TMS device used or as other TMS devices
(using newer technology) are developed and/or become FDA approved, details of the TMS
procedure may change over time. Consequently, treatment protocols should be reviewed
routinely.
For clinical management, details of the patient selection and evaluation process,
including who conducts the interview, documentation of a TMS responsive condition
and rationale for treatment, and recording of assessment tools and scales, can be listed.
Although there are no current mandatory laboratory or imaging tests required before TMS,
each program should consider whether there are any pre-TMS tests required or if tests are
strictly driven by indication or medical condition. A physical exam is also not required prior
to TMS, and programs need to decide when or what type of exam is done. If there are any
concerns regarding history of a suspected neurological condition, a thorough neurological
exam should be considered. Because TMS patients undergo a course of treatment over a
number of weeks, details of how patients are followed during this time should be outlined.
As noted earlier, one option is to ensure that patients are seen by the prescribing physician
at least every 1–2 weeks to evaluate outcome and tolerability so that changes can be made
in the treatment plan if needed. Also, nurses or assistants involved in the routine care of
TMS patients during the week should have a mechanism to communicate any concerns to
the physician in charge, and this expectation should be explicitly clear to team members
to ensure safety of TMS patients. Finally, this section should contain procedures on how to
manage side effects such as pain. Most importantly is a description of the program’s seizure
protocol and how this rare but potential adverse event is managed locally. This protocol may
include basic physical management to protect the patient’s airway and breathing, who to
call for medical assistance, instructions to contact EMS, and what to document (abnormal
preseizure activity, detail seizure/motor activity, duration of seizure, any injuries sustained,
and clinical status after the seizure). This seizure protocol can also be posted in the treat-
ment room for quick reference.
A TMS manufacturer section includes information about the maker of the TMS
device. This section contains contact information and procedures for ordering supplies and
who to call for maintenance and trouble-shooting. Finally, the important TMS literature
section is used as a resource for all team members to stay abreast of new advancements in the
clinical practice of TMS.
TMS Reimbursement
The spread of insurance coverage for TMS has been a slow process since the FDA approved
the first TMS device for depression in 2008, and this coverage has been sporadic over the
last five years in the United States. Costs of providing TMS encompass the facility overhead,
staffing, physician time, and TMS device costs. The fee charged for a TMS session is in the
range of $300–$400 (Reti, 2013). Without insurance coverage, many clinicians charge a fee
for service, and in many areas, access to TMS is limited. Those covered by Medicare also have
few options to receive TMS. Since there is no national coverage determination for TMS by
Medicare, TMS can be covered at the discretion of individual Medicare contractors based on
a local coverage determination (LCD; Services CfMM, 2013). There is a growing number
of Medicare contractors in certain regions of the United States that are developing policies
for TMS as a covered benefit. In early 2013, three Medicare contractors had TMS policies
that covered Alabama, Delaware, the District of Columbia, Georgia, Maine, Maryland,
Massachusetts, New Hampshire, New Jersey, Pennsylvania, Rhode Island, Tennessee, and
Vermont (CMS, L32055 (2013); CMS, L32228 (2012); CMS, L32834 (2012)). In addi-
tion, a number of other commercial healthcare providers across the United States have writ-
ten TMS policies.
The language for the FDA-approved TMS device and the indication of depression
focuses on a narrow window of only one failed antidepressant in the current episode indi-
cating early or mild treatment resistance (Neuronetics I, 2010). Interestingly, the criteria in
many policies vary and may actually require more severe treatment resistance before allow-
ing TMS. As an example, the LCD Medicare policies mentioned above list lack of signifi-
cant response to four medications from two antidepressant classes (CMS, L32055 (2013);
CMS, L32228 (2012); CMS, L32834 (2012)) as a criterion. For clinicians, it is important
to fully understand any TMS coverage provided by patients’ insurance policies and to review
this before prescribing TMS. If no coverage benefit is available, physicians and TMS team
members need to discuss fees and possibly even payment plan options for those who wish
to proceed but pay out of pocket. Even if a policy covers TMS, it is advisable to also obtain
preauthorization approval from the insurer, as this may further help clarify the actual TMS
benefit for patients and clinicians.
To facilitate billing of TMS, the American Medical Association (AMA) has assigned
Current Procedural Terminology (CPT) category I codes for TMS. Three codes are available
(see Table 6.1; American Medical Association, 2013). CPT code 90867 is used for the initial
TMS session when the motor threshold procedure is done, the treatment target is identified,
and dosing strategy is determined. In addition, this code is used for the entire first treatment
session. CPT code 90868 is used for subsequent daily treatment sessions. If a repeated motor
threshold is done for clinical reasons or per local protocol, CPT code 90869 is used to indi-
cate this procedure and for the entire treatment session that day. Both motor threshold codes
(90867 and 90869) should not be used in conjunction with each other or with the daily
treatment code (90868). Since 1992, the Centers for Medicare & Medicaid Services (CMS;
formerly Health Care Financing Administration) has used the resource-based relative value
scale model to quantify and reimburse for physicians services ( Johnson & Newton, 2002).
The model allows for the calculation of relative value units (RVUs) for every CPT code. As
of 2013, RVUs have not been assigned for TMS, but clinicians should monitor when the
RVUs become available.
Beyond depression, emerging clinical research has suggested that TMS might have a role
in a number of psychiatric and medical conditions such as anxiety disorders, bipolar disorder,
dementia, schizophrenia, pain, and tinnitus. However, more research is needed to establish
clear benefit for many of these conditions (Praharaj, Ram, & Arora, 2009; Vercammen et al.,
2009; Wassermann & Zimmermann, 2012). Any use of TMS for these clinical situations
would be deemed off label. TMS practitioners who venture into targeting different brain
regions or treating different disorders other than those approved may face difficulties similar
to those faced by prescribers of expensive medication for an off-label use. Preauthorization
may be needed or the treatment may not be covered at all.
Two strategies will help with changing policies. If TMS is prescribed even if the treat-
ment is not covered, use of the appropriate CPT codes when billing patients contributes to
the database on the use of TMS. This type of information is used by CMS and insurers and
can potentially impact policy development. Second, advocating for the safe and effective use of
TMS locally is a strategy to consider. Examples of advocacy that can be done include educating
the public about TMS and providing letters of support for the use of TMS to local insurers.
TABLE 6.1 CPT Codes for TMS
CPT Code Details
90867 Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment;

initial, including cortical mapping, motor threshold determination, delivery and
management of treatment
(Report only once per course of treatment)
(Do not report 90867 in conjunction with 95928, 95929, 908068, 90869)
90868 Therapeutic repetitive transcranial magnetic stimulation (TMS)
treatment: subsequent delivery and management, per session
90869 Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment;
subsequent motor threshold re-determination with delivery and management
(Do not report 90869 in conjunction with 90867 or 90868)
CPT is copyrighted by the American Medical Association.

Conclusion
When developing a TMS program, it is not sufficient to simply learn about the biological
mechanisms of TMS and the basic procedure. Much planning is involved to successfully
provide the best care and service for patients. Design of an excellent program entails creat-
ing thorough administrative protocols, policies, and operating procedures that become the
framework for all that TMS team members do. Finally, the use of TMS technology in clinical
situations appears to be a rapidly evolving field, with newer TMS strategies and devices on
the horizon. TMS program leaders must be constantly vigilant of the latest advances.
References
American Medical Association. (2013). CPT: current procedural terminology, professional edition. Chicago,
IL: American Medical Association.
Beam, W., Borckardt, J., Reeves, S., & George, M. (2009). An efficient and accurate new method for locating the
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7
Measurement-Based Care
in Transcranial Magnetic
Stimulation Practice
Shawn M. McClintock and Guy Potter
Introduction
The US Food and Drug Administration (FDA) recently approved the use of transcranial
magnetic stimulation (TMS) for the treatment of major depressive disorder (MDD) in
those patients who have failed one (O’Reardon et al., 2007) antidepressant treatments.
The studies documented clinical efficacy through the use of detailed measurements across
time with specified depression symptom severity scales. Thus, the provision of TMS was
guided by weekly clinical assessments. For example, if a patient showed improved or wors-
ening clinical status based on the objective clinical depression rating scale, treatment was
altered to either provide fewer or more sessions, respectively. Such practice is referred to as
measurement-based care, which involves the use of psychometrically sound instruments,
in conjunction with clinical knowledge, to provide systematic evaluation of an identified
outcome to generate evidence and guide therapeutic intervention (Garland, Kruse, &
Aarons, 2003).
The use of measurement-based care has received substantive empirical sup-
port (Trivedi & Daly, 2007; Trivedi et al., 2006; Harding, Rush, Arbuckle, Trivedi,
& Pincus, 2011). Indeed, it can be used to integrate research findings into clinical
practice, rationally guide treatment decision-making, optimize clinical outcome,
and help maximize the risk/benefit ratio of the therapeutic regimen. Although
measurement-based care tends to be routine in the management of chronic medical
illnesses, it is not standard in psychiatric practice (Harding et al., 2011). Thus, this
chapter underscores the need to include measurement-based care when guiding the
delivery of TMS in clinical practice.
M e a s u r e m e n t -B a s e d C a r e in T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n P r ac t i c e | 83
Implementing Measurement-Based Care
A major component of measurement-based care consists of integrating rating scales with
the clinical decision-making process. As each clinical therapeutic setting is unique, the
treatment team will need to determine practice guidelines for the implementation of
measurement-based care. Particular to the rating scales, following the recommendations of
Harding et al. (2011), they should be psychometrically sound, specific to the clinical patient
population and disease, and practical for the clinical setting.
Psychometric Considerations of the Chosen

Measures
Given the many depression severity measurement scales in clinical and research practice, it
is prudent to choose an instrument with excellent psychometric properties. A focus should
be placed on reliability, validity, and sensitivity to change. For reliability, the measure
should have high internal consistency and test–retest reliability. Internal consistency reli-
ability provides an index of whether the scale items together reflect a single unidimensional
aspect of the disease (e.g., depression) or whether the items reflect multiple dimensions
(e.g., anxiety, anhedonia, somatic complaints). Test–retest reliability provides an index of
repeated assessment consistency. Regarding validity, the measure should have convergent,
concurrent, and divergent validity. High convergent validity demonstrates that the measure
is associated with other measures of the same construct, and concurrent validity provides an
index that the measure documents the same construct at the same time as another related
measure. Last, high divergent validity demonstrates that the measure does not assess other
constructs.
Patient-Centered Considerations
Patient considerations in psychometric testing include tolerability, comprehension, and cul-
tural/demographic validity. Most depression measures reviewed here can be completed in
roughly the same amount of time, though those with more items may require additional time
relative to those with fewer items. Nonetheless, to our knowledge, none have been reported
to increase burden of time. In general, the measures described below should be compre-
hensible to patients with basic reading proficiency. However, if low literacy is present, the
clinician-rated scales may be more valid and preferred for the assessment.
With respect to participant age, different scales were created to maximize detection of
depression symptomatology along a developmental continuum including children, adoles-
cents, adults, and elderly adults. For instance, children and elderly adults present with differ-
ent depressive symptoms, thus the depression scale needs to match the specific age group. For
instance, due to age-related medical illnesses, certain rating scales may misattribute medically
attributable somatic symptoms to depression in elderly adults (Linden, Borchelt, Barnow, &
Geiselmann, 1995). Although most outcome studies with depressed older adults have used
rating scales that can be generally applied to the adult population, age-specific measures may
provide more sensitive outcome data if the items content more accurately reflects age-related
symptomatology of depression.
An under researched area is the variability in clinical ratings related to ethnic and
cultural differences on depression scales. For instance, some research has suggested that
there is considerable variation in the endorsement of suicidal ideation and somatic com-
plaints across cultures (Cusin, Yang, Yeung, & Fava, 2010). Many of the scales reviewed
in this chapter have been translated into multiple languages; consequently, there is lim-
ited cross-cultural research regarding the psychometric properties. Although there is
no compelling evidence that these scales have performed poorly in clinical trials across
different countries (Cusin et al., 2010), further research is needed to provide conclusive
information.
Practical Considerations for Clinical Use

In measurement-based care, there is interest in detecting the presence or absence of a mood
disorder in response to treatment. However, a more realistic goal is to track depression sever-
ity changes in response to treatment. Thus, an ideal instrument is sensitive to change across a
range of depression severity and is stable across different samples. If administered by a clini-
cian, it should have high interrater reliability to ensure that change is due to symptom change
and not variability in rater judgment. As most measures fall in the broad range of 10–20
minutes, time and tolerability are roughly comparable for measures reviewed here. We sug-
gest that it may be useful to have both clinician and self-reported measures in which case
instruments with dual forms have advantages. Where cost is an issue, instruments that are in
the public domain may be preferred.
Depression Severity Measures

There are many available depression symptom severity measures, in many formats, and
with different dimensional structures to assess only the construct of depression (uni-
dimensional) or multiple neuropsychiatric constructs such as depression, anxiety, and
physical ailments (multidimensional; McClintock, Haley, & Bernstein, 2011). Of
importance to measurement-based care implementation, these rating scales vary in terms
of item content, length of administration, and whether the assessment is administered
by a trained certified clinician or is completed by the patient. In TMS research, the
primary depression rating instruments included in the pivotal trials (O’Reardon et al.,
2007; Janicak et al., 2008) included the Hamilton rating scale for depression (HRSD),
Montgomery–Asberg depression rating scale (MADRS), Beck depression inventory-II
(BDI-II), and the 30-item inventory of depressive symptomatology-self report
(IDS-SR30). Other important depression symptom severity rating instruments to focus
on include those that were developed from a global health perspective, which include the
original and revised versions of the Center for Epidemiologic Studies depression scale
(CESD, CESD-R) and the patient health questionnaire (PHQ-9) and those tailored
to specific populations such as the children’s depression rating scale-revised (CDRS-R)
for children and adolescents and the geriatric depression scale (GDS) for elderly adults
(Table 7.1).
TABLE 7.1 Depression Symptom Severity Rating Measures
Instrument Name Scale Versions Number of Items Rating Metric Symptom Domain Content Languages Cost
Depression Measures Included in the TMS Pivotal Investigations

Hamilton rating scale Clinician-rated There are multiple 3-point scale Affective, somatization-anxiety, Multiple Free
for depression versions with (0, 1, 2) and cognitive, suicide, insomnia, weight/
items ranging 5-point scale appetite change, libido, sadness,
between 6 and 31 (0, 1, 2, 3, 4) psychomotor, obsessive-compulsive,
paranoia, self-critical
Montgomery–Asberg Clinician-rated 7-point scale Sadness, tension, insomnia, decreased Multiple Free
depression rating scale (0, 1, 2, 3, 4, 5, 6) appetite, concentration, lassitude,
anhedonia, pessimism, suicide
Beck depression Self-report 21 4-point scale Cognitive, behavioral, affective, Multiple Purchase from
inventory-II (0, 1, 2, 3) somatic Pearson Assessment (www.
pearsonassessments.com)
Inventory of Clinician-rated, 30 4-point scale Insomnia, sad mood, appetite/ Multiple Free
depressive self-report (0, 1, 2, 3) weight change, concentration, outlook,
symptomatology suicidal ideation, involvement, energy/
fatigability, psychomotor function,
anxiety, mood reactivity, mood quality,
anhedonia, libido, self-criticalness
Quick inventory Clinician-rated, 16 4-point scale Insomnia, sad mood, appetite/weight Multiple Free
of depressive self-report (0, 1, 2, 3) change, concentration, outlook, suicidal
symptomatology ideation, involvement, energy/
fatigability, psychomotor function
Global Health Perspective Depression Measures
Center for Self-report 20 5-point scale Depressive affect, somatic symptoms, Multiple Free
Epidemiologic Studies (0, 1, 2, 3, 4) positive affect, interpersonal relations
depression scale
(continued )
TABLE 7.1 (Continued)
Patient health Self -report 9 4-point scale Interest, appetite change, sleep change, Multiple Free
questionnaire-9 (0, 1, 2, 3) sad mood, suicide, concentration,
self-esteem, energy, self-critical,
psychomotor disturbance
Depression Measures for Specific Populations
Children’s depression Clinician-rated 17 6-point scale Impaired school work, difficulty having English Purchase from Western
rating scale-revised (0, 1, 2, 3, 4, fun, social withdrawal, sleep change, Psychological Services
5) and 8-point appetite change, fatigue, irritability, (www.wpspublish.com)
scale excessive guilt, low self-esteem,
(0, 1, 2, 3, 4, 5, depressed mood, morbid/suicidal
6, 7) ideation, excessive crying, depressed
facial affect, listless speech, hypoactivity
Geriatric depression Self-report Original version, 2-point scale (0, 1) Lowered affect, somatic concern, Multiple Free
scale (GDS) 30;short cognitive complaints, functional
version, 15 impairments, feelings of discrimination,
lack of future orientation, decreased
self-esteem
Depression Measures Included in the TMS

Pivotal Investigations
HRSD
The HRSD (Hamilton, 1960) was introduced in 1960 and is the most commonly used
observer rating of depression symptoms. In addition, it has been the primary outcome mea-
sure in a number of TMS investigations (Kearns et al., 1982). The most common versions
used with respect to psychometric evaluation include the 17 (HRSD-17) and 24 (HRSD-24)
item versions. The HRSD-24 version is often used in clinical research, but most of the psy-
chometric data are based on the HRSD-17. The HRSD was designed for use in MDD to
quantify the results of the clinical psychiatric interview (Hamilton, 1960). In practice, it is
used as an index and to assess change in depression symptom severity. The HRSD is designed
to be administered by a clinician and is formatted as a checklist of items on a scale of 0–4 or
0–2. The HRSD-17 total score ranges from 0 to 52, and the total score ranges from 0 to 75
for the HRSD-24. Widely accepted cutoff ranges for the HRSD-17 are as follows: >23, very
severe; 19–22, severe; 14–18, moderate; 8–13, mild; and <7, normal (Kearns et al., 1982).
An HRSD-17 total score <7 has been suggested as reflecting remission (Frank, 1991). The
evaluation takes about 15–20 minutes to administer and is publicly available in multiple
languages.
Reported reliabilities show variability, perhaps owing to the importance and chal-
lenges of maintaining standardized administration. It is noted, for instance, that internal
consistency reliability increases when the HRSD-17 is used in a structured interview
format (Potts, Daniels, Burnam, & Wells, 1990; Williams, 1988). Similar improvement
of interrater and test–retest reliability have been reported with structured interview
training (Kobak, Lipsitz, & Feiger, 2003). Although interrater reliability for the total
score is adequate, it has been found to be poor for several individual items (e.g., agita-
tion, genital symptoms, insight; Maier et al., 1988b). The HRSD-17 has good conver-
gent validity with other measures such as the MADRS, BDI-II, and IDS (Yonkers &
Sampson, 2008; Beck, Steer, & Brown, 1996; Bech et al., 1975). Most studies suggest
it is sensitive to change (Yonkers & Sampson, 2008); however, one study found that
change on the HRSD was more sensitive to changes in anxiety than to depression (Maier
et al., 1988a).
There have been critical psychometric critiques of the HRSD. One major psychometric
critique of the HRSD is poor construct validity, reflecting the absence of core diagnostic
items reflected in the 4th edition, text revision of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV-TR) (2000) diagnosis of MDD, such as anhedonia, low mood
reactivity, and reduced concentration (Yonkers & Sampson, 2008; Bagby, Ryder, Schuller, &
Marshall, 2004). Another critique is that anxiety-related questions on the scale may reduce
specificity to depression. A third major critique comes from the application of modern psy-
chometric methods (i.e., Rasch analysis) to the HRSD-17 items, which showed that hierar-
chical ranking of the individual items varied across study samples (Maier, 1990). This result
suggested that HRSD items might not be suitable for comparison of across-study samples.
One response to this problem was the introduction of a six-item HRSD version that fits
Rasch models (Bech et al., 1981; Licht, Qvitzau, Allerup, & Bech, 2005) and assesses the
core symptoms of depression.
The HRSD is one of the oldest and most widely used scales for depression, but it
presents a number of limitations, including lack of some core depression symptoms, poor
item comparability across samples, and questionable divergent validity from general anxiety
symptoms. It is also important to note that there have been many variations and modifica-
tions generated for the HRSD; thus adherence to a specific form and administration proto-
col is important in clinical and research settings.
MADRS
The MADRS has been used as the primary outcome measure in several TMS treatment
studies (Avery et al., 2008; O’Reardon et al., 2007; Lisanby et al., 2009). The intent
of the MADRS is to measure depression severity, with an explicit goal of being highly
sensitive to change in depression severity between placebo and psychotropic medication
in treatment studies (Montgomery & Asberg, 1979). Another goal of the MADRS was
to make it usable by professionals who have limited specific psychiatric training. This
clinician-rated scale is composed of 10 items rated on a scale of 0–6, with anchor items
at two-point intervals, with a total score range of 0–60. A MADRS score >31 differenti-
ates individuals with severe depression from more moderate levels of severity (Muller,
Himmerich, Kienzle, & Szegedi, 2003), while the following broad set of cutoffs was
suggested by Snaith and colleagues (1986): >34, severe; 20–34, moderate; 7–19, mild;
and 0–6, normal. Poznanski, et al. (2002) recommended an optimal cut off of <10 for
remission. Completion time is 10–15 minutes. Although the clinician-rated version is
the standard, there is a nine-item self-rated version (minus item 1, “Apparent Sadness”)
that is highly correlated with the original (Svanborg & Asberg, 2001). The MADRS
is copyrighted by the British Journal of Psychiatry, but is publicly available in multiple
languages.
Internal consistency reliability estimates for the total MADRS score range from
0.76 to 0.95 (32, 33), which were improved with the introduction of a structured inter-
view guide (Williams & Kobak, 2008). Interrater reliability was reported to range from.
89 to .97 in the original study; however, evidence of decreased reliability among a het-
erogeneous group of raters (psychiatrics, psychologists, psychiatric nurses, and students)
suggested possible weakness in this regard (Cusin et al., 2010). Content validity is con-
sidered strong, with coverage of all core symptoms of depression with the exception of
psychomotor retardation (Maier et al., 1988a). A correlation between the MADRS and
clinical version of the IDS was reported as 0.81 (Montgomery, 2000). The MADRS
has shown good concurrent validity with the HRSD (.80 to .90; Muller et al., 2003;
Hamilton, 2000), and both measures appear broadly comparable in their detection of
symptom change (Maier et al., 1988a).
The advantages of the MADRS are a relatively brief, widely used scale with adequate
psychometric properties that assesses most core features of depression. In addition to the
standard version, there is a self-report version with nine of the original items. A disadvantage
is that is does not include items related to melancholic and atypical depressive features, which
may be important in assessment of some patients.
BDI-II
The goal of the original BDI and BDI-II was to measure behavioral features of depression,
assess depression severity, and assess change over time. It is a widely used self-report screen for
depression in normal populations and for assessing severity in depressed patients (Furakawa,
2010) Item content of the BDI was originally drawn from observations made by patients
during psychotherapy, though there was a substantial revision to scale items with the intro-
duction of the BDI-II (Beck, Steer, & Brown, 1996). The BDI-II is composed of 21 items,
each item reflecting four statements on a scale of 0–3; however, the items of sleep and appe-
tite each have a seven-item scale. The BDI-II is traditionally used as a self-report inventory,
where individuals respond based on the preceding 2 weeks. The total score range is 0–63.
Conventions for estimating include the following: 29–63, severe; 20–28, moderate; 14–19,
mild; and 0–13 normal (Beck et al., 1996). Completion time is 5–15 minutes. It is described
as written at a 5th-grade reading level and is available in English and Spanish. Copyright
compliance requires that it be purchased from the test publisher (Pearson Assessments;
http://www.pearsonassessments.com).
There is a large body of psychometric data on the original BDI compared to the BDI-II,
but BDI data should not be extrapolated to the BDI-II due to its substantial revision. The
BDI-II manual reports internal consistency reliabilities >.90 across outpatient, primary
care, and medical populations (Beck et al., 1996). Test–retest data are appraised as sparse
(Furakawa, 2010), but the BDI-II manual reports 1-week test–retest reliability of .93 in a
sample of 26 outpatients referred for depression. The BDI-II has shown convergent validity
(r = 0.71) with the HRSD (Beck et al., 1996).
The BDI-II is a well-regarded and widely used self-report questionnaire of depression
symptom severity with adequate psychometric properties. Item content includes more cog-
nitive appraisal items than other questionnaires, which may be an advantage or disadvantage
depending on the application and patient population.
IDS
The design of the IDS and Quick IDS (QIDS) was to assess the severity of depressive symp-
toms (Rush, Gullion, Basco, Jarrett, & Trivedi, 1996; Trivedi et al., 2004). Both the IDS and
QIDS are available in clinician-rated (IDS-C) and self-rated (IDS-SR) versions, though this
review focuses primarily on the IDS-SR that was used in the pivotal TMS trial. The IDS-SR
assesses each of the criterion symptoms of DSM-IV codified MDD, and there is also item
content to capture melancholic and atypical features. It can be used to screen for depression
as well as to assess symptom severity. The IDS is composed of 30 items on a scale of 0–3 with
a total score range of 0–84. Conventions for rating depression severity are as follows: <12,
normal; 12–23, mildly ill; moderately ill, 24–36; 37–46, moderately to severely ill, and ≥47,
severely ill. Conversions are available to equate the total scores among the IDS, HRSD, and
MADRS (Rush et al., 2003). The IDS takes 15–20 minutes to complete and is available for
free download (www.ids-qids.org) in multiple languages.
Psychometric studies of the IDS-SR report a Cronbach’s α = .94 for a sample of both
depressed and controls and α = 0.75 for depressed only (Rush et al., 1996). The IDS-SR
total score was found to be highly correlated with the HRSD-17 (Rush et al., 1996). A study
by Corruble et al. (1999) suggested possible higher sensitivity to change compared to the
MADRS, which was attributed to the broader range of scores and item scaling.
The IDS-SR is a psychometrically sound depression scale that measures core features of
depression as well as melancholic and atypical features. The number of items and wide score
may make it more sensitive to mild depression severity. It also has the advantage of a matched
clinician-rated version.
Global Health Perspective Depression Measures

CESD
The CESD was developed in the late 1970s (Radloff, 1977), revised in 2004 (CESD-R;
Eaton, Muntaner, Smith, Tien, & Ybarra, 2004), and is one of most well known measures
given its use in large-scale epidemiologic studies. The CESD consists of 20 items that assess
depressive domains of sad mood, anhedonia, insomnia, decreased appetite, low self-esteem,
poor concentration, hopelessness, and helplessness. The scale is rated on a four-point item
scale (0, absence of symptom; 1, mild; 2, moderate; 3, severe) and has a total range of
0 to 60. Higher scores are indicative of greater depression severity, with a cutoff of 15 mean-
ing mild to moderate severity and 21 severe depression. The psychometric properties of
the CESD have been found to be optimal with high internal consistency in community
(Cronbach’s α = 0.85) and psychiatric (Cronbach’s α = 0.90) samples (Radloff, 1977; Santor,
Zuroff, Ramsay, Cervantes, & Palacios, 1995). The CESD-R was created to assess the depres-
sive domains of the DSM-IV, but maintained a length of 20 items on a 4-point scale. Thus,
there is equivalence in scores between the CESD and CESD-R. The revised version also has
optimal psychometric properties including high internal consistency (Cronbach’s α = 0.92),
convergent validity with other psychiatric measurement scales, and was found to be unidi-
mensional (Van Dam & Earleywine, 2011). The CESD and CESD-R are available for free
download (http://cesd-r.com/about-cesdr/) in multiple languages and in clinician-rated
and patient self-report versions.
PHQ-9
The PHQ-9 was originally part of the primary care evaluation of mental disorders
(PRIME-MD) and developed to provide a brief depression screening instrument that assesses
the nine depressive symptom domains of the DSM-IV (Kroenke, Spitzer, & Williams, 2001).
The PHQ-9 consists of nine items that are rated on a four-point scale, where 0 indicates
absence of symptom, 1 mild, 2 moderate, and 3 severe. The total score ranges from 0 to 27,
with a score of 5 suggesting mild depression, 10 moderate, 15 moderate to severe, and 20
severe. Last, there is an item that asks the patient to indicate if there are any employment,
social, or functional difficulties. The PHQ-9 has been found to have optimal psychometric
properties with high internal consistency (Cronbach’s α = 0.83), high test–retest reliability,
convergent validity, and it has a unidimensional construct (Cameron et al., 2008a, 2008b).
A score of 10 or greater was found to have 88% sensitivity and 88% specificity for MDD.
The self-report PHQ-9 is available for free download (http://www.phqscreeners.com/) in

multiple languages.
Depression Measures for Specific Populations

CDRS-R
The CDRS was first introduced in the late 1970s (Poznanski, Cook, & Carroll, 1979) and
was later revised (CDRS-R) in 1996 (Poznanski & Mokros, 1996). The scale was devel-
oped to capture depressive symptoms that are prominent in children and adolescents aged
of 6–12 years. The CDRS-R is a 17-item scale that is typically administered by a clinician
with the patient and parent(s) present in order to document the depressive symptoms such
as sad mood, irritable mood, sleep problems, low self-esteem, and suicidality. The items are
rated on two scales, with some rated on a six-point scale with a range of 0–5 points and
others on an eight-point scale with a range of 0–7 points. The total score ranges from 0 to
113 and can be converted to a standard T-score, where a score of >40 is indicative of the
presence of MDD. The CDRS-R has optimal psychometric properties with high internal
consistency (Cronbach’s α = 0.85), interrater reliability (r = 0.92–0.95), test–retest reli-
ability (r = 0.78), and convergent validity (Poznanski & Mokros, 1996). While it has been
used in many large-scale studies (e.g., the Treatment for Adolescents with Depression Study,
2004; Treatment of SSRI-Resistant Depression in Adolescents Study [Brent et al., 2008], it
could prove to be a lengthy interview process and may produce false-positive rates of MDD
in patients with chronic medical illnesses. The instrument is available for purchase from
Western Psychological Services (wpspublish.com) in only the English language.
GDS
The GDS was created to assess those depressive symptoms that are predominantly observed
in elderly adults in order to maximize specificity and minimize artificial inflation due to
other comorbid medical or psychiatric conditions (Yesavage et al., 1982). Further, the GDS
was tailored to be user friendly by phrasing items in a yes/no format to answer a question,
thereby increasing interpretability and rate of test completion. The GDS assesses multiple
depressive symptoms including sadness, changes in sleep and appetite, psychomotor distur-
bances, decreased concentration, indecisiveness, hopelessness, worthlessness, and suicidality.
There are two versions of the GDS, a long version with 30 items and a short version with
15 items (Sheikh & Yesavage, 1986). On both versions, each item is rated on a two-point
scale with 0 and 1 indicating symptom absence or presence, respectively. For the long ver-
sion, a score of 10–19 indicates the presence of mild depressive symptoms and a score of
>20 suggests severe depressive symptoms. On the short version, a minimum score of 5
indicates the presence of depressive symptoms. While this scoring system provides a simplis-
tic method to detect depressive symptoms, it does not allow for comprehensive interpreta-
tion of depressive symptom severity. For example, the GDS will note the presence of sad
mood, but the severity level remains unclear regarding if it is mild, moderate, or severe. This
information is important, particularly if multiple depressive symptoms are present, in order
to document the qualitative severity level of each symptom and determine changes across
time with treatment. Further, while the GDS has sound psychometric properties including
high sensitivity and specificity, it may not be valid in elderly adults with cognitive difficul-
ties (Burke, Roccaforte, & Wengel, 1991). The GDS is available for free download (http://
www.stanford.edu/~yesavage/GDS.html) in multiple languages and for various electronic
platforms (e.g., computer, smartphone).
Screening for Neuropsychologic Function

In addition to the domain of antidepressant outcome, clinical investigations of TMS have
also assessed the domain of neuropsychological function (see Table 7.2). For the TMS study,
the primary instrument used to screen for global cognitive function was the mini mental
state examination (MMSE). Other commonly used neuropsychology screening instruments
include the second edition of the MMSE (MMSE-2) and the Montreal cognitive assessment
(MoCA).
MMSE/MMSE-2
The intent of the MMSE (Folstein, Folstein, & McHugh, 1975; Folstein, Folstein, &
Fanjiang, 2001) was to provide a brief standardized assessment of cognitive status to assist a
broader clinical assessment of cognitive function, particularly cognitive change. It is widely
used to detect and track cognitive change, especially in the context of dementia, but is not
recommended as a tool for diagnosing dementia. The MMSE is composed of 30 items ratio-
nally grouped into domains including orientation, (memory) registration, attention and
TABLE 7.2 Neurocognitive Screening Instruments
Instrument Name Versions Domain Content Languages Cost
Dementia rating 2 (original, Orientation, attention, English Purchase from

scale, 2nd edition alternate) verbal and visual memory, Psychological Assessment
language, motor function, Resources (www.parinc.
executive function, verbal com)
fluency, conceptualization
and abstraction ability
Mini mental state 1 Orientation, attention, Multiple Purchase from
examination memory, language, motor Psychological Assessment
function Resources (www.parinc.
com)
Mini mental state 2 (red, Orientation, attention, Multiple Purchase from
examination-2 blue) processing speed, memory, Psychological Assessment
language, motor function Resources (www.parinc.
com)
Montreal cognitive 3 (7.1, Orientation, attention, Multiple Free
assessment 7.2, 7.3) memory, confrontation
naming, language,
abstraction ability, executive
function
Repeatable 4 (A, B, Processing speed, attention, English, Purchase from Pearson
battery for the C, D) verbal and visual memory, Spanish Assessment (www.
assessment of visuospatial construction, pearsonassessments.com)
neuropsychological confrontation naming,
status verbal fluency
concentration, (memory) recall, language, and visual construction. The total score ranges
from 0 to 30. A cutoff of 24 is often presented as an indication of dementia, but the sensitiv-
ity and specificity of this cutoff varies across samples and particularly by age, ethnicity, and
education level (MacDowell, 2006). The MMSE takes approximately 10 minutes to admin-
ister, can be administered by trained staff, and is relatively easy to score. The MMSE is copy-
righted, requires purchase (Psychological Assessment Resources, Inc.; http://www4.parinc.
com), and is available in multiple languages.
Internal consistency of the MMSE is moderate but variable, with Cronbach’s α ranging
from 0.55 to 0.96; however, reliability of the total score is higher and reaches correlations
>0.80 (Foreman, 1987; Salmon, 2008). Interrater reliability is high. Test–retest reliability is
adequate and higher over brief retest intervals (i.e., 1 day) than longer intervals (MacDowell,
2006). With respect to convergent validity, the MMSE is correlated with performance on
multiple neuropsychological and functional measures.
An advantage of the MMSE is that it is used in many studies because of its brevity and is
regarded as a “lingua franca” for cognitive status. While it is generally regarded as able to detect
moderate and severe cognitive decline, it has limitations in the detection of mild or subtle
cognitive dysfunction due to a low ceiling of difficulty; narrow range of cognitive abilities
assessed; and differential sensitivity to age, education, and ethnicity (Tombaugh & McIntyre,
1992). The MMSE has limitations in MDD and other neuropsychiatric conditions (Faustman
et al., 1990), in part, because of limited assessment of the types of executive function and infor-
mation processing speed deficits that characterize cognitive dysfunction in MDD.
MMSE-2 (Folstein, Folstein, White, & Messer, 2010) was recently introduced, and
incorporated advances to overcome limitations of the original version. The MMSE-2 con-
sists of three different lengths including a brief, standard, and expanded form. Each version
has two versions referred to as the blue and red forms in order to minimize practice effects
with repeat assessments. The brief version only measures orientation, and registration and
recall of simple words for a total of 16 points. The standard version is similar to the original
MMSE and measures global cognitive functions including orientation, attention, confron-
tation naming, memory, language, comprehension, and motor function, for a total of 30
points. The expanded version is suggested to be more sensitive to subcortical dementia by
also measuring story memory and processing speed, for a total of 90 points. The user manual
provides useful clinical information for the scores: sensitivity, specificity, percent correctly
classified, positive predictive power, negative predictive power, and reliable change for each
of the 3 versions of the scale. The authors of the MMSE-2 have undertaken a comprehensive
effort to address the limitations of the original MMSE. While this is promising, the newness
of the instrument precludes a critical review of the new scales in independent research, partic-
ularly with respect to MDD. The MMSE-2 is copyrighted, requires purchase (Psychological
Assessment Resources; http://www4.parinc.com/), and is available in multiple languages.
MoCA
The MoCA (Nasreddine et al., 2005) is a measure of global cognitive function that was
designed to assess similar domains of cognitive function as with the MMSE and MMSE-2
in <10 minutes. Importantly, it also measures executive function through items of cognitive
flexibility, abstraction, and phonemic fluency. The item content is organized into neuro-
cognitive domains, and total scores are produced for each domain and a total global score
that ranges from 0 to 30. A cutoff score of 26 was found to be highly sensitive in discerning
between normal cognitive function and mild cognitive impairment, with scores <26 indica-
tive of neurocognitive difficulties. The psychometric properties are optimal with high inter-
nal consistency (Cronbach’s α = 0.83), test–retest reliability (r = 0.92), and sensitivity and
specificity to neurocognitive impairment. A recent population-based study found that the
total score should be interpreted based on age and education levels (Rossetti, Lacrit, Cullum,
& Weiner, 2011). When designing the MoCA, the test developers also created two alternate
forms for repeat test administration in order to minimize practice effects at follow-up evalu-
ations. The MoCA is available for free download (http://www.mocatest.org/) in multiple
languages and with available alternate forms for select languages.
In addition to the above three screening instruments, other neuropsychological screen-
ing tools can be implemented in a host of clinical settings. These instruments include the
dementia rating scale-2nd edition (DRS-2; Jurica, Leitten, & Mattis, 2001) and the repeat-
able battery for the assessment of neuropsychological status (RBANS; Randolph, 2012). The
DRS-2 takes approximately 15–30 minutes to administer, with several pass/fail screening
items that direct the total number of administered items. It has often been used to provide
a more comprehensive dementia screen than the MMSE and has empirical scores on several
subscales of cognitive function. At least one study has suggested that it is superior to the
MMSE in screening for cognitive impairment in late-life depression, as it is more sensitive to
cognitive impairment that would be classified as normal on the MMSE.
The RBANS is more comprehensive in scope than the DRS-2 and takes approximately
30 minutes to administer, though it may take longer in older adults with MDD. It was
designed to be sensitive to dementia and has been used as an intermediate assessment across
multiple clinical populations, often bridging the gap between a brief cognitive status screen
and a comprehensive neuropsychological test battery. It also provides empirical scores for
subscales of cognitive function. These instruments have been well researched, have stable psy-
chometric properties, and may have unique advantages (e.g., better sensitivity to neurologic
impairment) depending on the clinical population.
Conclusion
As TMS continues to be implemented as an antidepressant treatment strategy, its rational use
will be guided by both clinical wisdom and measurement-based care. Such a strategy will prove
beneficial as it capitalizes upon the clinical knowledge of the treatment team, the therapeutic
relationship between the treatment team and the patient, and the use of rating instruments
to provide substantive evidence. Although measurement-based care is not standard clinical
practice in most of psychiatry, it is slowly becoming part of that practice and will continue to
grow given the many benefits. When implementing measurement-based care, the treatment
team should select those rating instruments that are psychometrically sound, specific to the
clinical patient population and disease, and practical for the clinical setting. The goal is for the
instruments to enhance, rather than hinder or burden, the therapeutic regimen.
Integrating measurement-based care with the provision of TMS confers many advan-
tages, including the systematic monitoring and assessment of change in depressive symptoms
during the course of treatment, provision of education to the patient regarding depressive
symptomatology, and evidence-guided treatment strategies for neuropsychiatric disease.
Continued research is needed regarding the antidepressant effects of TMS in order to address
many unanswered questions, such as optimal dosing strategies and length of treatment
courses. Integration of measurement-based care into clinical practices will help to provide
useful information to further guide the psychiatric field in refining TMS clinical practice.
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8
Neurophysiological
Measurements Associated
with Transcranial Magnetic
Stimulation
Natasha Radhu, Daniel M. Blumberger, Anosha
Zanjani, and Zafiris J. Daskalakis
Introduction
Transcranial magnetic stimulation (TMS) is a cutting-edge noninvasive neurophysiologi-
cal tool used to investigate the cortex in healthy and disease states (Barker, Jalinous, &
Freeston, 1985). Barker and colleagues first demonstrated that a single TMS pulse applied
to the motor cortex could activate cortical tissues associated with the hand or leg muscles
and that this activation could elicit motor-evoked potentials (MEPs) at the periphery cap-
tured through electromyography (EMG) recordings (Figure 8.1A; (Barker, Jalinous, &
Freeston, 1985)). TMS is a useful method to further understand the neurobiology of
cognitive function, behavior, and emotional processing (McClintock, Freitas, Oberman,
Lisanby, & Pascual-Leone, 2011). It involves the generation of a magnetic field through
the use of an electromagnetic coil connected to a TMS device, which induces an electrical
current in the brain (Wagner, Valero-Cabre, & Pascual-Leone, 2007). TMS is used as an
investigational tool as it assesses a variety of cortical phenomena including cortical inhibi-
tion (CI), excitation, and plasticity (Kujirai et al., 1993; Classen, Liepert, Wise, Hallett,
& Cohen, 1998). Assessing the cortical phenomena using TMS provides valuable insights
into the neurophysiological substrates underlying psychiatric and neurological disorders.
However, the restriction of such recordings to the motor cortex is of limited interest as the
pathophysiology of many neuropsychiatric disorders lies in other areas of the cortex. Thus,
evaluating the neurophysiology of brain regions that are more proximal to the underlying
phenotype (e.g., the dorsolateral prefrontal cortex [DLPFC]) is essential.
N e u r o p h y s i o l o g i ca l M e a s u r e m e n t s A s s o c i at e d with TMS | 99
Overview of TMS Technology

TMS capitalizes on the ability of time-varying magnetic fields to induce eddy currents in bio-
logical tissue via Faraday’s principle of electromagnetic induction. TMS fields pass through
the scalp unimpeded and noninvasively stimulate brain areas compared to more invasive
transcranial electrical stimulation (Hallett, 2000). Conventional approaches to measure
cortical neurophysiology involve stimulation of the motor cortex while using MEPs as the
primary dependent variable of interest, which is measured in the periphery through EMG.
Such approaches have been used to demonstrate important neurophysiological findings in
both healthy and disease states, which will be discussed in this chapter.
Applications of TMS
TMS has been used for both therapeutic and diagnostic purposes (Rossini & Rossi, 2007).
In relation to its diagnostic application, TMS provides a tool for assessing the timing of cor-
tical processes, cortico-cortical connectivity, CI, facilitation, plasticity, and the interaction
between cortical processes (Anand & Hotson, 2002; Chen, 2004; Daskalakis et al., 2004; Di
Lazzaro et al., 2004; Pascual-Leone, Walsh, & Rothwell, 2000; Sanger, Garg, & Chen, 2001).
In this section, inhibitory and excitatory TMS paradigms are discussed in the context of the
underlying neurophysiological mechanisms associated with each method.
Inhibitory TMS Paradigms

TMS can be used as a neurophysiological tool to measure CI, as evidenced by its association with
gamma-aminobutyric acid (GABA) inhibitory neurotransmission. These paradigms include the
cortical silent period (CSP; Cantello, Gianelli, Civardi, & Mutani, 1992), long-interval cortical
inhibition (LICI; Valls-Solé, Pascual-Leone, Wassermann, & Hallett, 1992), short-interval corti-
cal inhibition (SICI; Kujirai et al., 1993), and transcallosal inhibition (TCI; Ferbert et al., 1992).
CSP and LICI
CSP is a single-pulse paradigm measured by stimulating the contralateral motor cortex of a
moderately tonically active muscle (i.e., 20% of maximum contraction) with stimulus intensi-
ties of 110%–160% of the resting motor threshold (RMT) resulting in the interruption of
voluntary muscle contraction (Cantello et al., 1992; Figure 8.1B). The duration of the CSP is
typically measured from MEP onset to the return of any voluntary EMG activity, ending with
a deflection in the EMG waveform (Tergau et al., 1999). LICI refers to the pairing of a supra-
threshold conditioning stimulus (CS) followed by a suprathreshold test stimulus (TS) at long
interstimulus intervals (e.g., 50–100 msec), resulting in inhibition of the MEP produced by the
TS in the contralateral muscle (Valls-Solé et al., 1992). LICI is optimal when the CS precedes
the TS by 100–150 msec (Sanger et al., 2001; Figure 8.1C). CSP and LICI appear to be assess-
ing GABAB receptor-mediated inhibitory neurotransmission, as evidenced by pharmacologi-
cal studies (Siebner, Dressnandt, Auer, & Conrad, 1998; McDonnell, Orekhov, & Ziemann,
2006), the time course of the GABAB inhibitory postsynaptic potential (Siebner et al., 1998;
McCormick, 1989; Werhahn, Kunesch, Noachtar, Benecke, & Classen, 1999), and the supra-
threshold stimulation of the CS (Sanger et al., 2001). For example, administration of baclofen (a
GABAB receptor agonist) has been shown to enhance LICI (McDonnell et al., 2006) and CSP
(Siebner et al., 1998). Similarly, vigabatrin (a GABA analog) has also been shown to increase
LICI and CSP (Pierantozzi et al., 2004). LICI and CSP are associated with high intensities
that produce longer periods of inhibition as GABAB receptor-mediated responses have higher
activation thresholds and their inhibitory influence is longer (Sanger et al., 2001). Farzan et al.
(2010b) found that EMG measures of LICI were significantly correlated with the duration of
the CSP. Taken together, this evidence suggests that LICI and CSP are both related to GABAB
receptor-mediated inhibitory neurotransmission.
SICI
SICI is a paired-pulse inhibitory paradigm that involves a subthreshold CS set at 80% of the
RMT that precedes a suprathreshold TS, adjusted to produce an average MEP of 0.5–1.5 mV
peak-to-peak amplitude in the contralateral muscle (Kujirai et al., 1993; Figure 8.1D). To
measure SICI, conditioning stimuli are applied to the motor cortex before the TS at inter-
stimulus intervals between 1 and 4 msec, resulting in inhibition of the MEP response by
50% to 90%. Ziemann et al. (1996a) demonstrated that SICI is increased by medications
that facilitate GABAA inhibitory neurotransmission (e.g., lorazepam) in healthy individu-
als. Using computer simulations, Wang and Buzsaki (1996) showed that the synaptic time
constant for GABAA receptors ranges from 10 to 25 msec. This finding demonstrates that
SICI is related to GABAA receptor-mediated inhibitory neurotransmission, as evidenced by
the similar time course of the GABAA inhibitory postsynaptic potential. SICI is associated
with a low-intensity CS, producing shorter periods of inhibition. The GABAA receptor has a
lower activation threshold and its inhibitory influence is brief (Sanger et al., 2001).
TCI
TCI can be demonstrated by applying a CS to the motor cortex, which inhibits the size of
the MEP produced by the TS of the opposite motor cortex (Ferbert et al., 1992; Hanajima
et al., 2001). This result is consistent with animal studies which show that stimulation of
the motor cortex inhibits the contralateral motor cortex several milliseconds later (Chang,
1953; Asanuma & Okuda, 1962; Matsunami & Hamada, 1984). TCI can be observed at
interstimulus intervals between 6 and 50 msec (Ferbert et al., 1992; Gerloff et al., 1998).
Daskalakis and colleagues found that similar populations of inhibitory neurons might medi-
ate LICI and TCI (Daskalakis, Christensen, Fitzgerald, Roshan, & Chen, 2002). Therefore,
TCI may be related to GABAB activity. This is consistent with the finding that lorazepam
increased SICI but did not change TCI, suggesting that TCI is not related to GABAA activ-
ity (Pierantozzi et al., 2004).
Excitatory TMS Paradigms

TMS can also be used to examine cortical excitability, paradigms include MEP amplitude,
RMT, and intracortical facilitation (ICF). MEP amplitude is measured as the average
response to a series of pulses applied at a consistent TMS intensity or measured as the

increasing MEP size produced with increasing TMS intensity (referred to as a MEP response
curve; Zaaroor, Pratt, & Starr, 2003). RMT is defined as the minimal intensity that pro-
duces a MEP >50 μV in 5 of 10 trials in a relaxed muscle (Rossini et al., 1994). The RMT
depends largely on voltage-gated ion channels (Paulus et al., 2008). It has been shown that
drugs that block voltage-gated sodium channels, in particular anticonvulsants such as car-
bamazepine, lamotrigine, and losigamone, increase RMT (Ziemann, Lönnecker, Steinhoff,
& Paulus, 1996b). Finally, ICF is a paired-pulse paradigm that can be used to index excit-
atory activity in the motor cortex. In this paradigm, a CS is applied to the motor cortex
before the TS at interstimulus intervals between 7 and 20 msec. This results in an enhanced
MEP compared to that produced by the TS alone (Kujirai et al., 1993; Nakamura, Kitagawa,
Kawaguchi, & Tsuji, 1997; Figure 8.1E). It has been shown that ICF originates from excit-
atory postsynaptic potentials transmitted by N-methyl-D-aspartate glutamate receptors
(Nakamura et al., 1997). Pharmacological studies have demonstrated a decrease of ICF
by N-methyl-D-aspartate receptor antagonists such as dextromethorphan and memantine
(Ziemann, Chen, Cohen, & Hallett, 1998). Benzodiazepines such as lorazepam (a GABAA
agonist) decreases ICF (Ziemann et al., 1996a) and baclofen (a GABAB agonist) decreases
ICF (Ziemann et al., 1996b). However, research has demonstrated that ICF is not exclu-
sively mediated by excitatory interneurons but rather by a net balance between inhibition
and excitability (Daskalakis et al., 2004). For a review of the pharmacological effects on
inhibitory and excitatory TMS paradigms, see Paulus et al. (2008).
Motor Cortex TMS Studies in Psychiatric

Illnesses and Clinical Utility
Dysfunction of GABA inhibitory interneurons represents one of the most established
neurobiological findings in schizophrenia (SCZ), major depressive disorder (MDD),
obsessive-compulsive disorder (OCD), and bipolar disorder. A series of studies have reported
that TMS paradigms that generate a functional index of GABA inhibitory neurotransmis-
sion from the cortex of healthy human patients have demonstrated a distinct and consistent
pattern of deficiency in severe psychiatric disorders. These paradigms show high test–retest
reliability and large effect size differences between healthy and patient populations. These
tests are relatively easy to perform, inexpensive, and easy to interpret. Several lines of evidence
suggest that CI is impaired in these disorders. For example, previous TMS studies have dem-
onstrated deficits in CI assessed from the motor cortex (Figure 8.2) in patients with OCD
(Richter et al., 2012; Greenberg et al., 2000; Greenberg, Ziemann, Harmon, Murphy, &
Wassermann, 1998), MDD (Levinson et al., 2010; Lefaucheur et al., 2008; Bajbouj et al.,
2006; Fitzgerald et al., 2004), SCZ (Wobrock et al., 2008, 2009, 2010; Liu, Fitzgerald,
Daigle, Chen, & Daskalakis, 2009; Daskalakis et al., 2002, 2008; Fitzgerald et al., 2003;
Fitzgerald, Brown, Daskalakis, Kulkarni, 2002; Fitzgerald, Brown, Daskalakis, deCastella, &
Kulkarni, 2002), and bipolar disorder (Levinson, Young, Fitzgerald, & Daskalakis, 2007).
Furthermore, a recent metaanalysis (Radhu et al., 2013) found significant effect sizes for
decreased SICI, enhanced ICF, and reduced CSP within the OCD population. For MDD,
A B C
500 mV 500 mV
TS 20 ms 50 ms TS CS TS 50 ms
D E
2 mV 2 mV
10 ms 10 ms
CS TS CS TS
F I G U R E 8 . 1
Electromyography Recordings Produced by TMS. (A) A single TMS pulse is applied to the
motor cortex producing an MEP. (B) The cortical silent period: starts at the onset of the MEP and ends
with the return of motor activity. A suprathreshold TMS pulse is applied to the motor cortex while
the contralateral hand muscle is tonically activated. (C) LICI: a suprathreshold-conditioning stimulus
precedes a suprathreshold test stimulus by 100 ms, inhibiting the MEP produced by the test stimu-
lus. (D) SICI: a subthreshold conditioning stimulus precedes a suprathreshold test stimulus by 2 ms,
inhibiting the MEP produced by the test stimulus. (E) ICF: a subthreshold conditioning stimulus pre-
cedes a suprathreshold test stimulus by 20 ms, facilitating the MEP produced by the test stimulus.
Source: Reprinted from Radhu, N., Ravindran, L. N., Levinson, A. J., & Daskalakis, Z. J., Inhibition of the
Cortex in Psychiatric Disorders using Transcranial Magnetic Stimulation: Current and Future Directions,
Journal of Psychiatry and Neuroscience, Figure. S1: Surface electromyography recordings from a right
hand muscle Canadian Medical Association Journal November 2012, 37(6), pages 369–378. © Canadian
Medical Association 2012. This work is protected by copyright and the making of this copy was with
the permission of the Canadian Medical Association Journal (www.cmaj.ca) and Access Copyright. Any
alteration of its content or further copying in any form whatsoever is strictly prohibited unless otherwise
permitted by law.
Motor Response
0.5mV
20 ms
F I GUR E 8 .2 A single

TMS pulse is applied to the motor cortex, activating cortical tissues associ-
ated with the abductor pollicis brevis muscle and eliciting an MEP at the periphery captured through
electromyography.
the significant effect sizes were found for decreased CSP and SICI. Significant deficits in
SICI were shown in SCZ. These findings are in line with previous literature that suggests CI
deficits among psychiatric disorders. Collectively, these studies provide evidence to suggest
that impairments in GABA inhibitory neurotransmission are a ubiquitous finding in severe
psychiatric illnesses.
GABAergic inhibitory deficits are closely involved in the pathophysiology of SCZ,
MDD, OCD, and bipolar disorder. Nevertheless, the overall pattern of these deficits differs
among the diseases. TMS paradigms hold potential as biomarkers of psychiatric disorders
and treatment response. Biomarker development will lead to strategies that prevent manifes-
tation of the illness and increase our understanding of the underlying neurobiological mech-
anisms. However, further replication of findings is required. The use of TMS to establish
molecular engagement of novel psychopharmacological and somatic treatments (i.e., elec-
troconvulsive therapy [ECT], repetitive TMS, magnetic seizure therapy, transcranial direct
current stimulation, or cognitive behavior therapy), particularly within the GABA and gluta-
mate circuits, are other potential biomarker roles for these tests. Conceivably TMS measures
of GABAergic and glutamatergic functioning could be used as biological markers of novel
treatments that are aimed at enhancing inhibition or decreasing facilitation in the cortex.
Potential Clinical Applications

Overview of EEG
In the 1920s, the psychiatrist Hans Berger recorded brain waves from the surface of the human
scalp and coined the technique as electroencephalography (EEG; Swartz & Goldensohn,
1998; Buzsaki, 2006). Specifically in EEG, electrical activity of the cortex is monitored by
placing multiple electrodes along the scalp; these electrodes record electrical signals that are
primarily generated by coordinated output of neurons from the scalpal surface (Nunez &
Srinivasan, 2006). Cortical potentials recorded through EEG represent the oscillatory activ-
ity of underlying neuronal activity (Nunez & Srinivasan, 2006). Such recordings at rest can
be used clinically to diagnose tumors, seizures, encephalopathies, and brain death and can
be used as biological markers of neuropsychiatric illnesses (Sponheim, Clementz, Iacono, &
Beiser, 2000; Tot, Ozge, Comelekoglu, Yazici, & Bal, 2002; Venables, Bernat, & Sponheim,
2009; Babiloni et al., 2011). By contrast, when sensory stimuli are presented to patients,
evoked activity that is of greater electrical power is produced and recorded at the scalp sur-
face when compared to resting EEG recordings. Such activity can be used to evaluate the
neurophysiological mechanisms involved in the processing of emotional or cognitive stimuli.
Combined TMS and EEG

The past decade has seen significant developments in the concurrent use of TMS and EEG
to directly assess cortical network properties such as CI, excitability, and connectivity.
Simultaneous EEG recording during TMS stimulation was previously unattainable because
of the technological shortcomings of EEG amplifiers that would saturate for a long duration
due to the large artifact produced by the magnetic stimulation. For example, application of
a single TMS pulse would result in artifact lasting for several seconds after the pulse. Such
long-lasting artifact blocks the window of time during which neurophysiological processes
such as CI occur. Through advances in EEG amplifier technology, researchers have con-
ducted a series of studies to examine TMS paradigms in the motor cortex through simulta-
neous EEG and EMG as well as in frontal brain regions through EEG recordings.
A significant electromagnetic artifact field is generated by the TMS (at the site of stim-
ulation) and is several-fold larger than that produced by sensory-evoked potentials on EEG
recordings (Ilmoniemi et al., 1997). Several developments in EEG amplifier technology have
led to a reduction of this artifact. First, Ilmoniemi and colleagues (1997) reported that decou-
pling of the electrode from the amplifier at or immediately before TMS can markedly reduce
the impact of the TMS stimulus artifact on EEG recordings. This was achieved through a
sample-and-hold circuit that maintains amplifier output at a constant level during stimulus
delivery (Ilmoniemi et al., 1997). They showed that this modification permitted amplifier
recovery within 100 μsec after the TMS. Second, in a traditional alternating-current (AC)–
coupled EEG amplifier, the typical 500-mV and 50-μsec TMS pulse prevent the signal from
returning to zero immediately after the pulse. Rather, the signal that is recorded is followed
by a negative deflection that can take seconds to return to its initial state. With the intro-
duction of direct-current (DC)–coupled EEG amplifiers, this prolonged negative swing is
eliminated and immediately returns to its linear range after the stimulus stops. DC coupling
has become available only in recent years with the introduction of fast 24-bit analogue digi-
tal converter (ADC) resolution (i.e., 24 nV/bit) that is superior to the older 16-bit ADC
resolution that was limited to 6.1 μV/bit, a resolution that fails to limit the TMS stimulus
artifact. The third modification is to record EEG at very high sampling rates (e.g., 20 kHz)
to permit full characterization of the TMS pulse and limit the stimulus artifact that is pro-
duced on the recordings. By using any of these strategies, EEG recording can become TMS
compatible (for a review, see Ilmoniemi & Kicic, 2010). Furthermore, the EEG electrodes
used during TMS–EEG should satisfy the physical requirements to operate within the harsh
TMS environment. The electrodes must be designed with a small enough diameter to avoid
overheating or be affected by the forces that result from the induced TMS currents. Also,
the electrodes must be coated with suitable surface material to ensure a proper interface
with skin contact (Ilmoniemi and Kicic, 2010). It is suggested that the optimal electrodes
to record TMS–EEG are small silver/silver chloride pellet electrodes (e.g., to allow the mea-
surement of the electrical potential on the skin [Roth, Pascual-Leone, Cohen, & Hallett,
1992; Virtanen, Ruohonen, Näätänen, & Ilmoniemi, 1999; Ives, Rotenberg, Poma, Thut, &
Pascual-Leone, 2006).
There are several postprocessing procedures for removal of TMS-induced artifact from
the EEG recording, as extensively reviewed by Ilmoniemi and Kicic (2010). EEG amplitudes
greater than 100 µV and containing large artifacts from electromagnetic residuals, eye blinks,
eye movement, or muscle activity should be rejected. Alternatively, there are more superior
methods that enable the separation of brain signals from artifacts such as signal-space projec-
tion (Ilmoniemi and Kicic, 2010), independent component analysis (Korhonen et al., 2011;
Hamidi, Slagter, Tononi, & Postle, 2010), modeling of sources and artifacts (Ilmoniemi and
Kicic, 2010), and principal component analysis (Levit-Binnun et al., 2010; Litvak et al.,
2007. Offline procedures such as the use of filters to eliminate TMS-related artifact from
EEG have also been proposed; these procedures require further investigation (Morbidi et al.,
2007). There is one major limitation involved in using these postprocessing techniques, that
is, there is no way of verifying that brain activity is not being removed along with the artifact
components.
Advantages of TMS–EEG
There are four main advantages of using combined TMS–EEG in research studies. First, by
using TMS–EEG, investigators can study the mechanisms through which MEPs are gener-
ated and modulated. Second, online EEG recording allows for the possibility to evaluate the
effects of electromagnetic induction on cortical oscillatory activity to appropriately identify
the cortical oscillations that are closely associated with the TMS-induced MEP generation
and modulation. A third major advantage of combined TMS–EMG and EEG is the pos-
sibility to evaluate the cortico-cortical connectivity between motor cortices. Functional
connectivity between cortical regions (e.g., left and right motor cortices) is easily probed by
measuring the propagation of TMS-induced cortical responses. TMS–EEG methodologies
permit the investigation of the frontal brain areas that are more proximal to the underlying
phenotype (nonmotor regions of the cortex). For example, examining LICI in the DLPFC
enhances our understanding of the inhibitory mechanisms that underlie a cortical area that
is more closely associated with the pathophysiology of psychiatric disorders.
Rhythms of the Brain as Measured by EEG

Network oscillations are generated from the rhythmic and synchronized firing of output
neurons in the cortex. Oscillations can be recorded from the surface of the cortex through
EEG and are represented as five frequency bands. These bands include delta (1–3.5 Hz),
theta (4–7 Hz), alpha (8–12 Hz), beta (12.5–28 Hz), and gamma (30–50 Hz). Each fre-
quency band is related to different states. For example, the delta and theta bands are greatest
during deep sleep and are demonstrated during wakefulness in various pathological con-
ditions (e.g., tumors, Alzheimer’s disease [Huang et al., 2000; Babiloni et al., 2004, 2006;
Montez et al., 2009]). Alpha bands are greatest in the incipient stages of sleep, during low
arousal periods, and when individuals close their eyes. Beta oscillations show greatest activ-
ity during resting wakefulness. Gamma oscillations are associated with the most complex
cognitive demands, including information encoding, feature binding, as well as informa-
tion storage and recall (Tallon-Baudry, Bertrand, Peronnet, & Pernier, 1998; Meltzer et al.,
2008). Several studies have suggested that frontal cortical gamma oscillations are necessary
for working memory (Howard et al., 2003; Cho, Konecky, & Carter, 2006; Basar-Eroglu
et al., 2007; Barr et al., 2009, 2010, 2011). Functionally, gamma oscillatory activity has been
suggested to provide the temporal dimension in information encoding, whereby the success-
ful encoding of information depends on its arrival time relative to the gamma cycle (Fries,
Nikolic, & Singer, 2007). Interneuron activity mediated by GABA then shapes the time
course for prefrontal pyramidal activation (Constantinidis, Williams, & Goldman-Rakic,
2002) that is maximally activated when the fast-spiking interneurons are not firing (Wilson,
O’Scalaidhe, & Goldman-Rakic, 1994). GABA receptor activity is also responsible for the
generation (GABAA) and modulation (GABAB) of gamma oscillations (Wang & Buzsáki,
1996; Whittington, Traub, & Jefferys, 1995; Traub, Whittington, Colling, Buzsáki, &
Jefferys, 1996; Bartos, Vida, & Jonas, 2007; Brown, Davies, & Randall, 2007; Leung & Shen,
2007). Thus, GABA plays a critical role in the generation and modulation of gamma oscilla-
tions, which are vital in cognitive tasks.
Single-Pulse TMS Combined With EEG

Ilmoniemi and colleagues were one of the first research groups to use interleaved TMS–
EEG to investigate the effect of TMS on cortical excitability (Ilmoniemi et al., 1997). It was
demonstrated that TMS applied to the hand representation area of the human motor cortex
elicited a cortical response that spread to the adjacent ipsilateral area and to the homologous
regions in the opposite hemisphere. It was further shown that the application of TMS to
the visual cortex resulted in a similar pattern of signal propagation to the contralateral areas,
therefore, providing evidence that the cortical potentials following motor cortex stimula-
tion were less likely to be a result of peripheral sensory activation. This original experiment
resulted in a series of studies that further characterized the EEG substrate of cortical excit-
ability, inhibition, plasticity, and connectivity in those who are healthy (Esser et al., 2006;
Kähkönen et al., 2001, 2003; Komssi et al., 2002; Komssi & Kähkönen, 2006; Nikulin,
Kicić, Kähkönen, & Ilmoniemi, 2003; Paus, Sipila, & Strafella, 2001; Thut et al., 2003).
Paired-Pulse TMS Combined With EEG

Daskalakis et al. (2008) and Fitzgerald et al. (2008) were the first to demonstrate that record-
ing LICI (paired-pulse technique) through interleaved TMS–EEG was feasible in both the
motor cortex and DLPFC in those who are healthy. In the motor cortex, EEG measures
of LICI were represented by the reduction of cortical evoked activity in the electrode C3,
which best represents evoked activity in the hand area of motor cortex closest to the optimal
site of abductor pollicis brevis activation through TMS (Cui, Huter, Lang, & Deecke, 1999).
LICI was defined using the area under rectified unconditioned and conditioned waveforms
for averaged EEG recordings between 50 and 150 msec post test stimulus. This interval was
chosen because it represents the earliest artifact-free data (i.e., 50 msec post test stimulus)
and reflects the duration of GABAB receptor-mediated inhibitory post synaptic potentials
(i.e., 250 msec post conditioning stimulus; Deisz, 1999). There was a significant inhibi-
tion in mean cortical evoked activity through LICI compared to the test stimulus alone
in both the motor cortex and DLPFC (targeted through cortical coregistration methods;
Rusjan et al., 2010). Farzan et al. (2010b) has demonstrated the validity, replicability, and
test–retest reliability (Cronbach’s α >0.7) of LICI using the TMS–EEG method in both
the motor cortex and DLPFC. In this study, a significant correlation was found between
MEP suppression and suppression of cortical evoked EEG activity (Farzan et al., 2010b).
These results provide compelling evidence to suggest that TMS-induced EEG suppression is
related to GABAergic processes (i.e., GABAB inhibition), which mediate EMG measures of
LICI (Sanger et al., 2001; Siebner et al., 1998). Similar research was also developed through
experiments by Fitzgerald and colleagues (2009) who used equivalent methods and reported
maximal inhibition from 50 to 250 msec in DLPFC and from 50 to 175 msec in the parietal
lobe. They concluded that LICI might be recorded from several cortical regions with a time
course similar to that of known GABAB receptor-mediated inhibition.
More recently, Ferreri et al. (2011) also investigated the ability to record SICI and ICF
using TMS–EEG. In these experiments, SICI was recorded using an interstimulus interval
of 3 msec, while ICF was recorded using an interstimulus interval of 11 msec. These authors
demonstrated that significant inhibition could be reliably recorded in the motor cortex
through both EMG and EEG (recorded from the Cz electrode) and that these recordings
were correlated, suggesting that such measures are mechanistically related to those recorded
from peripheral hand muscles through EMG.
Assessing the Effects of TMS–EEG on Sleep

Massimini and colleagues (2005) investigated cortical effective connectivity during wake-
fulness and sleep using TMS with high-density EEG, evaluating the premotor cortex. They
found that during wakefulness, TMS induced a sustained response made of recurrent waves
of activity: time-locked high-frequency (20–35 Hz) oscillations followed by a few slower
(8–12 Hz) components that persisted until 300 msec. During stage 1 sleep, this TMS-evoked
response grew stronger and became shorter in duration. With the onset of non–rapid eye
movement (NREM), the TMS-induced brain response changed markedly. The initial wave
doubled in amplitude and lasted longer; however, no further TMS-locked activity could be
detected following this large wave. Based on these findings, they concluded a breakdown of
long-range effective connectivity during NREM sleep. Recently, Massimini et al. (2010) used
TMS with high-density EEG over the premotor cortex and found that during REM sleep, the
TMS-evoked brain response consisted of a sequence of fast oscillations during the first 150
msec similar to wakefulness. They also found that activity during stage 1 sleep replicated pre-
vious findings (Massimini et al., 2005). Using TMS-EEG in sleeping participants, Massimini
et al. (2007) demonstrated that TMS evoked a high-amplitude slow wave that originated
under the coil and spread over the cortex; this triggered slow waves during sleep was that
were state dependent. Regardless of stimulation site and intensity, TMS pulses evoked slow
waves during NREM and could not do so during wakefulness. Taken together, these findings
suggest that the effects of TMS–EEG are strongly dependent on the state of the activated
brain region (i.e., initial level of underlying cortical activity [Silvanto, Cattaneo, Battelli, &
Pascual-Leone, 2008; Silvanto, Muggleton, & Walsh, 2008; Silvanto & Muggleton, 2008;
Silvanto, Muggleton, Cowey, & Walsh, 2007; Silvanto & Pascual-Leone, 2008]).
Loss of Consciousness Studies

Similarly, Ferrarelli and colleagues (2010) indexed TMS-evoked EEG responses in wakeful-
ness compared to induced loss of consciousness using midazolam. Before injection of the
anesthetic, TMS pulses to the premotor cortex evoked a complex spatiotemporal pattern
of low-amplitude high-frequency activity. Conversely, following midazolam-induced loss of
consciousness, TMS pulses gave rise to high-amplitude low-frequency EEG potentials that
faded shortly after the stimulation. They concluded that a breakdown of effective cortical
connectivity was a key mechanism mediating midazolam-induced loss of consciousness.
More recently, using TMS-EEG, Rosonova et al. (2012) evaluated cortical effective connec-
tivity in patients emerging from a coma after a severe brain injury. In patients in a vegetative
state who were behaviorally awake (open-eyed) but unresponsive, they found that TMS trig-
gered a simple, local response, indicating a breakdown of effective connectivity similar to that
in unconscious, sleeping, or anaesthetized participants. In contrast, in minimally conscious
patients (who were nonreflexive), TMS triggered complex long-range activation in distant
cortical areas. Taken together, the literature indicates that TMS–EEG, by evaluating effec-
tive connectivity, can be used to assess sleep, wakefulness, anesthetized state, and vegetative
states.
How Can We Apply Combined TMS and EEG

in Psychiatric Disorders?
Several studies have used combined TMS and EEG to examine the pathophysiology of
psychiatric disorders. For example, Ferrarelli et al. (2008) stimulated the premotor cortex
using combined TMS–EEG and reported reduced TMS-evoked gamma oscillations within
the first 100 msec post stimulus in patients with SCZ. These gamma oscillations were sig-
nificantly attenuated in amplitude and demonstrated less synchrony in the fronto-central
regions. The authors concluded that there was an intrinsic dysfunction in frontal thalamocor-
tical circuits in SCZ. Similarly, Farzan et al. (2010a) assessed patients with SCZ, bipolar dis-
order, and healthy controls using the TMS–EEG paired-pulse technique (i.e., LICI) in both
the motor cortex and DLPFC. They found that, overall, LICI (1–50 Hz) in SCZ patients
did not differ significantly in any region when compared with bipolar patients and healthy
controls. However, when the evoked EEG response was filtered into different frequency
bands, they found a significant deficit in the inhibition of gamma oscillations (30–50 Hz)
in the DLPFC of SCZ patients relative to patients with bipolar disorder and healthy controls
(Figure 8.3). They also found no differences in the inhibition of other oscillatory frequen-
cies in the DLPFC or in the motor cortex between the three groups. The authors con-
cluded that this selective deficit in the inhibition of gamma oscillations demonstrates that
the DLPFC is a region in the brain that is closely related to the pathophysiology of SCZ.
Furthermore, Frantseva and colleagues (2012) demonstrated an increased TMS-induced
cortical activation (in the gamma frequency range) that spread across the cortex, as mea-
sured by TMS-EEG in SCZ. However, in healthy controls, this activation faded away soon
after stimulation. Recently, Hoppenbrouwers et al. (2013) showed that psychopathic offend-
ers suffer from dysfunctional inhibitory neurotransmission in the DLPFC, as measured
through combined TMS and EEG assessing LICI. The authors concluded that the impair-
ments demonstrated in the study might render the psychopath unable to regulate impulses,
in turn, subjecting them to a disinhibited, antisocial life. Casarotto et al. (2011) investigated
Healthy Controls Patients with Schizophrenia
Healthy inhibition Deficits in the inhibition

of gamma (30–50 Hz) of gamma (30–50 Hz)
oscillations in the DLPFC. oscillations in the DLPFC.
F I GUR E 8 .3 Patients
with schizophrenia have selective deficits in the inhibition of gamma (30–50 Hz)
oscillations in the DLPFC compared to healthy controls using interleaved TMS and electroencephalography.
frontal cortex excitability in healthy young and elderly individuals compared to patients with
Alzheimer’s disease. They found that TMS-evoked potentials were not affected by physiolog-
ical aging, unless an abnormal cognitive decline (Alzheimer’s disease) was associated. They
demonstrated that frontal cortex excitability, identified as early and local cortical response
to TMS, was reduced in elderly patients with Alzheimer’s disease. However, this was not
significantly different between healthy young and elderly individuals. Casarotto and col-
leagues (2013) were the first to evaluate MDD patients using TMS–EEG in order to assess
neuroplastic responses before and after their last administration of ECT. They demonstrated
that there was a significant increase of frontal cortical excitability (in every patient) after a
course of ECT when compared to baseline, suggesting that ECT produces synaptic potentia-
tion. These above-mentioned studies illustrate that TMS–EEG can be used as a clinical tool
to characterize the underlying neurobiological dysfunction and to evaluate the neurophysi-
ological effects of treatments over time.
Functional connectivity between cortical regions is easily evaluated by measuring the
propagation of TMS-induced cortical responses (via TMS–EEG). Voineskos et al. (2010)
evaluated TMS-evoked potentials using single-pulse TMS and studied its effects on inter-
hemispherically homologous regions in healthy participants. They found an inverse rela-
tionship between microstructural integrity of callosal motor fibers with TMS-induced
interhemispheric signal propagation from left to right motor cortex. Also, they demon-
strated an inverse relationship between microstructural integrity of the fibers of the genu
of the corpus callosum and TMS-induced interhemispheric signal propagation from left to
right DLPFC. These findings support a role for the corpus callosum in preservation of func-
tional asymmetry between homologous cortical regions in healthy participants. The authors
concluded that delineation of the relationship between corpus callosum microstructure
and interhemispheric signal propagation in neuropsychiatric disorders, such as SCZ, might
reveal a novel neurobiological mechanism of pathophysiology. Taken together, these studies
demonstrate the abnormal functional integration of neuronal systems associated with psy-
chiatric disorders. The above evidence points to important new areas in which TMS–EEG
can provide valuable neurophysiological insights in neuropsychiatric disorders.
Future Directions and Conclusions

Advances in cortical stimulation and cortical recording techniques over the past few decades
have allowed for the systematic and noninvasive investigation of the neurophysiological pro-
cesses from the cortex in humans. TMS is a cutting-edge technique that allows for the inves-
tigation of the cortical phenomena in both motor and nonmotor regions to further elucidate
the pathophysiology of psychiatric disorders. Among such advancements, concurrent TMS
and EMG recordings have been instrumental in identifying and probing cortical processes
that underlie the generation and modulation of MEPs. Although the evidence is still limited,
research to date suggests that disorders such as SCZ, MDD, OCD, and bipolar disorder are
characterized by specific deficits in CI and abnormalities in cortical excitability. However, the
published studies are not entirely consistent. Factors that may play a role in the discrepant
results include small sample sizes, differences in TMS parameters used, use of heterogeneous
populations, and presence of comorbid illness. Further, medications may affect outcomes of
TMS measures, and it is likely that different classes of psychotropics may do this in unique
ways. As such, the inclusion of medicated individuals on various classes of psychotropic agents
in these studies is a significant confounder of results. Addressing these issues systematically in
future research would allow greater confidence in results and provide a more stable evidence
base for elucidating biological markers and mechanisms involved in psychiatric illnesses. The
ability to evaluate physiological response profiles of different oscillatory frequencies in response
to TMS combined with EEG may ultimately serve as a key technique for evaluating biological
markers in psychiatric illnesses. In conclusion, combined TMS and EEG will continue to pro-
vide a deeper insight into the neurobiological underpinnings of psychiatric disorders.
Acknowledgements
This work was supported, in part, by the Canadian Institutes of Health Research (CIHR)
Clinician Scientist Award (ZJD), CIHR Fellowship (DMB). This work was funded by an
operating award from the Ontario Mental Health Foundation (ZJD), by Constance and
Stephen Lieber through a National Alliance for Research on Schizophrenia and Depression
Lieber Young Investigator award (ZJD) and Independent Investigator Award (ZJD). NR
received funding from the Ontario Graduate Scholarship Program. ZJD received external
funding through Neuronetics and Brainsway Inc, Aspect Medical and a travel allowance
through Pfizer and Merck. ZJD has also received speaker funding through Sepracor Inc and
served on the advisory board for Hoffmann-La Roche Limited. This work was supported
by the Grant and Temerty Family through the Centre for Addiction and Mental Health
Foundation.
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9
Stimulation in the Treatment
of Psychiatric and Neurological
Disorders
Paul Fitzgerald
Introduction
Repetitive transcranial magnetic stimulation (rTMS) has been investigated and applied
across a range of neuropsychiatric disorders. The greatest amount of translational research
has investigated the use of rTMS in the treatment of patients with major depressive disorder.
However, a substantive series of studies have also investigated the use of rTMS across schizo-
phrenia, anxiety, pain, stroke, and a range of other disorders. The evidence base and rationale
for these other applications varies considerably, as will be outlined in this chapter. Although
clinical services are predominantly developed around the use of rTMS in depression, it is
likely that the indications for this technique will progressively expand in coming years as the
evidence base for use in other disorders progressively increases.
rTMS in Depression: Standard Approaches

Initial Research
Initial studies assessing the use of TMS in depression applied single pulses to the vertex, typi-
cally with limited benefit (Grisaru, Yaroslavsky, Abarbanel, Lamberg, & Belmaker, 1994).
This tentative start reflected initial concerns about the overall safety of the application of
rTMS. As this became better established, investigators began to explore more substantive
therapeutic protocols. The application of rTMS also began to be informed by the growing
neuroscience understanding of brain abnormalities in patients with depression.
The initial therapeutic application of rTMS involved high-frequency stimulation to
the left dorsolateral prefrontal cortex (DLPFC). This approach has persisted to current
times, although a range of other methods for rTMS treatment of depression have also been
explored. The use of high-frequency left DLPFC stimulation was initially suggested by stud-
ies that demonstrated changes in left DLPFC blood flow using positron emission tomog-
raphy (PET) in patients with depression (George, Ketter, & Post, 1994). The left anterior
prefrontal cortex had also been implicated in the etiology of depression from studies explor-
ing the development of the illness following strokes and in electroencephalography (EEG)
studies exploring prefrontal activation in patients with depression. It was hypothesized that
by increasing prefrontal activity with high-frequency rTMS, the left prefrontal deficit in
metabolism could be corrected, producing a reduction in depressive symptoms.
Initial studies exploring the antidepressant effects of rTMS were, by modern standards,
relatively short and used low rTMS doses. The studies were typically 1 to 2 weeks duration
and applied no more than 20 rTMS trains per day (George et al., 1997; Pascual-Leone,
Rubio, Pallardo, & Catala, 1996). In spite of these limited stimulation parameters, clear anti-
depressant effects were evident, leading to a rapid and widespread expansion of interest in
exploring the use of rTMS.
Since the mid-1990s, more than 30 randomized double-blind controlled trials have
explored the application of high-frequency rTMS applied to the left DLPFC. The majority
of these trials have demonstrated greater antidepressant effects with active stimulation than
sham, although negative studies have also been published.
Over time, there has been a progressive evolution in the stimulation parameters applied
in studies. Trial duration has increased from 1 to 2 weeks to 4 weeks and then to 6 to 9 weeks
in some studies (Fitzgerald & Daskalakis, 2011). The number of stimulation trains applied
per day and the overall number of stimulation pulses has also substantially increased over
time. A variety of frequencies have been used ranging from 5 to 25 Hz, although 10 Hz is
most commonly used. The 10 Hz stimulation parameters typically involve stimulation trains
between 4 and 5 seconds duration. Finally, initial rTMS studies used stimulation intensity
less than the resting motor threshold (often 90%). This has progressively increased such that
most trials today use 120% of the resting motor threshold as standard stimulation intensity.
Multi-Site Trials
Although many of the rTMS studies conducted to date have been small, investigator-initiated
trials, several larger-scale multisite trials have been performed. An equipment manufacturer
that had patent protection over a modified rTMS coil design sponsored the first study. This
study involved the randomization of more than 300 medication-free patients to either active
or sham stimulation (O’Reardon et al., 2007). Treatment was provided on a daily basis for
6 weeks and could be continued during a 3-week taper period. Seventy-five trains at 10 Hz
were provided daily at a relatively high intensity. A nonidentified sham stimulation coil
system was used to ensure the blinding of both patients and clinicians.
The results of this trial are somewhat complex. There was a significant benefit of active
over sham stimulation across most trial outcome measures. However, a significant difference
was not seen on the a priori nominated primary outcome measure (the Montgomery–Asberg
depression rating scale) on the full study sample. Significant differences between active and
sham stimulation were seen when the sample was limited to patients who had only failed to
T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n in the T r e at m e n t of P s y c h i at r i c | 119
respond to a single antidepressant medication in their current episode. The results of the sec-
ondary analysis were used to achieve device registration for this patient group in the United
States in late 2008. Notably, treatment was generally well tolerated in this trial, with a low
overall dropout rate.
A second multisite trial that was independently sponsored included 199 patients
receiving 3000 10-Hz pulses applied on a daily basis for 3 weeks, with a possible 3-week
extension for partial responders (George et al., 2010). Active stimulation produced a greater
percentage of patients who achieved remission of depressive symptoms than sham stimula-
tion, although the overall rates of remission in both groups were low (14.1% versus 5.1%).
Treatment was also very well tolerated in this trial.
Meta-Analyses
A number of metaanalyses have summarized the results of rTMS trials in depression. These
generally demonstrate a clear and substantial antidepressant benefit of active stimulation
over sham. For example, the analysis by Schutter (2009) involved 30 trials and 1164 patients.
This study found a highly significant effect of active treatment compared to placebo, indi-
cated by the average reduction in depression severity scores (P < 0.00001) with a moderate
effect size (0.39). The benefit of treatment was not dependent on the degree of preexist-
ing medication resistance. The intensity of stimulation also did not affect overall outcomes.
Analyses indicated that the findings in this analysis were robust to typical biases that can
influence metaanalyses.
TMS and ECT
A series of studies have also compared rTMS to electroconvulsive therapy (ECT; Pridmore,
Bruno, Turnier-Shea, Reid, & Rybak, 2000; Janicak et al., 2002; Grunhaus et al., 2000;
Grunhaus, Dannon, & Schreiber, 1998; Eranti et al., 2007; Rosa et al., 2006). Unfortunately,
the majority of these studies have serious limitations that restrict the conclusions that can be
drawn from them. Most of these studies had small sample sizes, which limit their capacity to
show differences between two active treatments. There also were significant differences in the
way treatment was applied; a number of trials compared a fixed number of unilateral rTMS
sessions to a nonfixed number of both unilateral and bilateral ECT treatment sessions. Many
of these trials showed no differences in outcomes between the two treatments, although it
is possible that this simply reflects a lack of study power. Several studies found a treatment
advantage of ECT, either for patients with depression as a whole (McLoughlin et al., 2007) or
for a subgroup of patients with depression with psychotic symptoms (Grunhaus et al., 1998).
rTMS in Depression: Other Approaches

Low Frequency Right Sided rTMS
Although the vast majority of rTMS research has explored the use of high-frequency rTMS
applied to the left DLPFC as described above, a complementary body of research has
explored a number of other rTMS treatment options. The most substantial group of studies
explored the use of low-frequency stimulation (usually 1 Hz) applied to the right DLPFC.
This approach was, in part, motivated by early EEG studies that demonstrated changes in
prefrontal activity between right and left DLPFC in depression. As indicated above, these
studies can be interpreted as showing a reduction in left prefrontal activity, but alternatively
can also be interpreted as demonstrating an increase in the right DLPFC activity in depres-
sion. Therefore, it was considered that low-frequency stimulation may produce antidepres-
sant effects in reducing right DLPFC activity.
Studies using low-frequency rTMS have been conducted since 1999. Low-frequency
stimulation is typically provided at 1 Hz. Initial studies used multiple short typically
1-minute, trains. More recent low-frequency studies typically apply a single lengthy rTMS
1-Hz train, often of 15 to 20 minutes duration. The majority of the studies conducted to
date have shown positive antidepressant effects. This finding was confirmed in a recent
metaanalysis that demonstrated an effect size of 0.634 for active compared to sham stimu-
lation (Schutter, 2010). This result appears robust, as approximately 120 negative studies
would be required to render the effect significant. Notably, within this analysis, the author
compared the effect size apparent with low-frequency right-sided stimulation to that found
in a previously conducted metaanalysis of left-sided high-frequency stimulation (Schutter,
2009). No differences were found, suggesting similar clinical effects. This is consistent with
the findings of studies directly comparing the clinical effects of high-frequency left- and
low-frequency right-sided rTMS (Fitzgerald et al., 2003). Response to one type of rTMS
does not seem to exclude the possibility of response to the other (Fitzgerald et al., 2009).
It is also possible that there are differences in the patients who would respond to either
type, such that treatment could be individualized, but this has not been systematically
investigated.
Bilateral rTMS
A third potential method of application of rTMS involves bilateral stimulation. Bilateral
simultaneous high-frequency stimulation does not appear to have antidepressant efficacy
(Loo et al., 2003). A significant number of studies have explored the use of sequential bilat-
eral rTMS, using both low-frequency right-sided and high-frequency left-sided stimulation.
Studies have demonstrated that sequential bilateral rTMS produces greater antidepressant
effects than sham stimulation (Fitzgerald et al., 2006). However, a series of recent trials
have suggested that response to bilateral stimulation is not greater than response to unilat-
eral stimulation (Fitzgerald et al., 2011, 2012; Pallanti, Bernardi, Di Rollo, Antonini, &
Quercioli, 2010).
All approaches described above tend to support a model of depression that proposes
left prefrontal hypoactivity or right prefrontal hyperactivity and the use of stimulation
paradigms to reverse this. However, it is worth noting that several studies have suggested
that low-frequency stimulation applied to the left DLPFC may have antidepressant effects
(Feinsod, Kreinin, Chistyakov, & Klein, 1998; Padberg et al., 1999; Speer et al., 2009). One
study also suggested that bilateral 1-Hz stimulation appears to have antidepressant activity
(Fitzgerald et al., 2011). Therefore, the specificity of frequency and laterality assumed in
some of the traditional rTMS models may not be as tightly linked to clinical response as has
traditionally been assumed.
Other Approaches
Finally, there are a number of other, more experimental approaches to the use of rTMS treat-
ment in depression. For example, the priming approach involves combining low-intensity
high-frequency stimulation usually applied at 6 Hz with subsequent 1-Hz, low-frequency
stimulation. Preliminary research has reported that the antidepressant effects of this in the
right DLPFC may be greater than standard low-frequency stimulation alone (Fitzgerald,
Herring, et al., 2008). A second alternative approach is the use of patterned stimulation,
most typically of the theta burst type. Theta burst stimulation (TBS) typically involves the
application of a very short (e.g., three pulses) high-frequency bursts, usually at 50 Hz. These
bursts are repeated at theta frequency (usually 5 Hz). Continuous TBS typically decreases
and intermittent TBS increases cortical excitability (Paulus, 2005). Significant cortical
effects appear to be achieved with very short stimulation paradigms using TBS, although the
antidepressant benefits of these have not been substantially established to date.
rTMS in Depression: Issues With Treatment

Provision
There are a number of significant, unresolved issues in the application of rTMS treatment in
depression. First, almost all rTMS research has concentrated on the acute phase of treatment,
that is, producing an amelioration of depressive episode rather than exploring the long-term
impact of rTMS treatment on the course of major depressive disorder. Studies conducted to
date suggest that there is a significant likelihood of relapse in the 6 to 12 months following
acute treatment with rTMS that resulted in clinical response or remission. In a sample of
more than 200 patients who had successfully undergone rTMS treatment, 80% had relapsed
by 6 months (Cohen, Boggio, & Fregni, 2009). Limited information is available on the value
of strategies that may be used to prevent relapse. No systematic trials have explored the use of
medication in preventing relapse post rTMS, although research post ECT suggests that the
combination of lithium and antidepressant treatment is more likely to be successful than an
antidepressant alone (Sackeim et al., 2001; Rehor et al., 2009). A few preliminary studies have
reported on methods for the provision of maintenance rTMS as a relapse prevention strategy.
This most often involves the provision of weekly or fortnightly single rTMS sessions, often
with a decrease in session frequency over time (O’Reardon, Blumner, Peshek, Pradilla, &
Pimiento, 2005; Li, Nahas, Anderson, Kozel, & George, 2004). An alternative approach
involves a short burst of multiple treatment sessions, provided less frequently (Fitzgerald,
Grace, Hoy, Bailey, & Daskalakis, 2012). In addition, it is possible to provide acute rTMS
treatment at the point of development of depressive relapse. Several studies have indicated
that patients who have responded initially to rTMS are likely to respond again to subsequent
treatment sessions following relapse (Demirtas-Tatlidede et al., 2008; Fitzgerald, Benitez,
et al., 2006a; Janicak et al., 2010).
A second substantive issue with the provision of rTMS treatment relates to the method
of treatment targeting. Most applications of rTMS in depression have used a relatively sim-
plistic method for localizing DLPFC that involves localizing the motor cortical site for hand
muscles and then measuring 5 cm anterior in a parasagittal line over the scalp surface (the
5-cm method; Schönfeldt-Lecuona et al., 2010). However, research has demonstrated that
this is likely to be inaccurate in a significant percentage of patients (Herwig, Padberg, Unger,
Spitzer, & Schönfeldt-Lecuona, 2001). Several other localization alternatives are possible,
most using various forms of neuro navigation. Neuronavigational techniques typically require
the coregistration of the location of an individual’s head to some form of digitized brain
scan. One study explicitly demonstrated that treatment targeting based on neuroanatomical
localization (to a brain site at the junction between Brodmann areas 9 and 46, as defined
by Rajkowska and Goldman-Rakic, 1995) results in a superior antidepressant response to
rTMS localized using the 5-cm method (Fitzgerald, Hoy, et al., 2009). Researchers are also
exploring whether treatment targeting based on functional imaging may be of clinical utility
(Herwig et al., 2003; Martinot et al., 2010; Herbsman et al., 2009).
A third issue relates to the type of rTMS coil used in treatment studies. Most clinical
trials to date have used standard figure-8 coil designs that produce stimulation of approxi-
mately 1 to 2 cm² of tissue but limited cortical penetration. More recently, technology has
been developed to produce substantially deeper stimulation, for example, of the more orbital
medial, cingulate, or insula cortical regions. This so-called deep TMS is done with a novel
coil design that produces more widespread cortical stimulation with substantial penetra-
tion into deeper brain regions (Deng, Peterchev, & Lisanby, 2008; Salvador, Mir, Roth, &
Zangen, 2007). Preliminary data appear promising (Rosenberg, Shoenfeld, Zangen, Kotler, &
Dannon, 2010), and controlled trials are underway.
Treatment of Bipolar Disorder

Although some clinical trials investigating the effectiveness of rTMS treatment have excluded
patients with bipolar disorder, a number of trials conducted to date have included mixed
samples. Within trials of this type, no analyses have suggested a bipolar diagnosis is a nega-
tive predictor of the likelihood of clinical response. In fact, in one study patients with bipo-
lar disorder had a substantially higher response rate (almost 70%) than the overall group
(51%; Fitzgerald, Huntsman, Gunewardene, Kulkarni, & Daskalakis, 2006). However, most
studies do not provide this sort of separate analysis. In addition, only a limited number of
studies have specifically investigated rTMS effects in bipolar depression (Dolberg, Dannon,
Schreiber, & Grunhaus, 2002; Nahas, Kozel, Li, Anderson, & George, 2003; Dell’Osso et al.,
2009, 2011; Harel et al., 2011). None of these studies are of large enough scale to make defin-
itive conclusions about the application of rTMS in bipolar depression, although it is typically
assumed that response rates are likely to be similar to those seen in unipolar depression.
Several studies have also investigated the use of rTMS treatment for mania. An ini-
tial study found greater antimanic effects with high-frequency stimulation applied to the
right DLPFC compared to the left (Grisaru, Chudakov, Yaroslavsky, & Belmaker, 1998).
Antimanic effects of high-frequency right-sided stimulation also were suggested in two sub-
sequent case series (Michael & Erfurth, 2004; Saba et al., 2004). However, the results of two
sham controlled trials have been contradictory, with one demonstrating antimanic effects
(Praharaj, Ram, & Arora, 2009) and one demonstrating no difference between active and
sham stimulation in the treatment of mania (Kaptsan, Yaroslavsky, Applebaum, Belmaker, &
Grisaru, 2003).
Treatment of Anxiety Disorders

Obsessive Compulsive Disorder
Considerable interest has accumulated in the potential use of rTMS in the treatment of
obsessive-compulsive disorder (OCD), especially given the well-defined nature of the
frontal–subcortical brain network abnormalities in this disorder (Harrison et al., 2009).
However, the research conducted to date does not provide a universally positive suggestion
of therapeutic efficacy. The first study exploring rTMS effects in OCD found a greater reduc-
tion in OCD symptoms with right prefrontal stimulation than that seen with left prefron-
tal stimulation or stimulation at a control site (Greenberg et al., 1997). Subsequent studies
using left DLPFC stimulation have predominately produced negative results (Sachdev, Loo,
Mitchell, Mcfarquhar, & Malhi, 2007; Sarkhel, Sinha, & Praharaj, 2010), although stud-
ies exploring high-frequency right-sided stimulation have not been adequately conducted to
exclude this as a therapeutic target. Low-frequency stimulation approaches have also been
predominately negative when applied either to the right (Alonso et al., 2001) or left DLPFC
(Prasko et al., 2006).
Preliminary research has suggested that targets outside of DLPFC may be more prom-
isingly approached. For example, one study found therapeutic benefits greater than sham
with 1-Hz stimulation applied to the left orbitofrontal cortex (Ruffini et al., 2009). A second
novel approach has produced positive results by targeting the bilateral supplementary motor
area (Mantovani et al., 2006, 2010).
Other Anxiety Disorders

Only a limited body of research has explored the use of rTMS in posttraumatic stress dis-
order (PTSD), and studies conducted to date have used relatively divergent methods.
Neuroimaging-based models of PTSD have suggested that hypoactivity of the DLPFC and
associated hyperactivity of the amygdala are linked to underlying illness symptoms and that
right-sided changes are predominant in PTSD. A high-frequency approach to right-sided
stimulation therefore has some therapeutic rationale (Paes et al., 2011). Studies have inves-
tigated a variety of stimulation paradigms including low- and high-frequency stimulation
applied to the left DLPFC and low- and high-frequency stimulation applied to the right
DLPFC (Rosenberg, Shoenfeld, Zangen, Kotler, & Dannon, 2010; Cohen et al., 2004;
Boggio et al., 2010; Watts, Landon, Groft, & Young-Xu, 2012). Right-sided high-frequency
stimulation has shown the greatest therapeutic promise in two studies that evaluated stimu-
lation to both hemispheres or compared different frequencies of stimulation applied to the
right DLPFC (Cohen et al., 2004; Boggio et al., 2010).
Two randomized controlled trials explored the use of 1-Hz stimulation applied to the
right DLPFC in panic disorder but with contradictory results. In the first study, no signifi-
cant difference was seen between active and sham stimulation in 15 medication-resistant
patients (Prasko et al., 2007). The second study, in a slightly larger sample size (n = 25),
found significant differences in response between active and sham stimulation (Mantovani,
Aly, Dagan, Allart, & Lisanby, 2012). Low frequency right-sided rTMS has also been evalu-
ated in one open-label study in generalized anxiety disorder (Bystritsky et al., 2008). Six of 10
patients met remission criteria for reduction in anxiety symptoms following treatment based
on fMRI-based localization.
Treatment of Schizophrenia
A number of rTMS approaches have been used in the potential treatment of schizophrenia
or its symptoms. These approaches have mostly targeted either the prefrontal cortex, with
an emphasis on the treatment of negative symptoms, or the temporoparietal cortex, in an
attempt to ameliorate auditory hallucinations.
The first rTMS studies in schizophrenia applied low- or high-frequency stimula-
tion to the DLPFC and evaluated whether this had an impact on the global symptoms of
the disorder. The results of these initial studies were generally negative or found changes
mainly in noncore symptoms (Geller, Grisaru, Abarbanel, Lemberg, & Belmaker, 1997;
Feinsod et al., 1998; Klein et al., 1999). Most studies using high-frequency DLPFC stim-
ulation targeting positive symptoms of schizophrenia failed to produce positive results
(Holi et al., 2004; Sachdev, Loo, Mitchell, & Malhi, 2005; Hajak et al., 2004), and the
lack of benefit with this approach was confirmed in a recent metaanalysis (Freitas, Fregni,
& Pascual-Leone, 2009).
Negative Symptoms
More recently, interest has been focused on the potential use of prefrontal stimulation in
the treatment of negative symptoms, based on the observation that hypoactivation in pre-
frontal regions is thought to correlate with negative symptoms (Andreasen et al., 1997).
Thus, it was hypothesized that high-frequency rTMS applied to the DLPFC might improve
negative symptoms by increasing cortical activity (Cohen et al., 1999). A number of studies
have explored this approach, although these have almost universally been limited by small
study samples and relatively short durations of treatment application. Many of these studies
showed a significant advantage of active over sham stimulation (Hajak et al., 2004; Prikryl
et al., 2007; Jandl et al., 2005; Goyal, Nizamie, & Desarkar, 2007), although negative studies
have also been conducted (Holi et al., 2004; Mogg et al., 2007; Novak et al., 2006). Notably,
several of the positive studies (Prikryl et al., 2007; Prikryl et al., 2007; Jandl et al., 2005) used
higher stimulation intensity (>100% of the standard resting motor threshold), and one study
used a longer treatment duration (15 days) than the negative studies (10 days; Prikryl et al.,
2007). A major confound in these trials is the potential amelioration of depressive symptoms
with rTMS misinterpreted as an improvement in negative symptoms. One of these two posi-
tive studies also carefully controlled for the possible confound of improved depressive symp-
toms using scores on the Calgary depression scale for schizophrenia as a covariate; improved
depression did not account for the observed improvement in negative symptoms (Prikryl
et al., 2007).
Auditory Hallucinations
The second major use of rTMS in schizophrenia is the application of low-frequency stimula-
tion, typically 1 Hz, to the temporoparietal cortex (TPC) in patients with persistent refrac-
tory auditory hallucinations. This application was suggested by imaging studies linking
the pathophysiology of auditory hallucinations to hyperactivity in the left TPC (Shergill,
Brammer, Williams, Murray, & Mcguire, 2000; Silbersweig et al., 1995). Initial studies pro-
vided only brief courses of stimulation but showed a decrease in the frequency and intensity
of auditory hallucinations (Hoffman et al., 1999, 2000). A larger, controlled study, of 9 days
of low frequency left-sided (LFL) stimulation of the TPC found a substantial and significant
reduction in auditory hallucinations compared to sham. Furthermore, this improvement was
sustained in more than half of the improved patients at 15 weeks post treatment (Hoffman
et al., 2003). A considerable series of trials has subsequently evaluated this approach. Two
recent metaanalyses found a benefit of active over sham stimulation with a medium to large
effect size (Freitas et al., 2009; Tranulis, Alisepehry, Galinowski, & Stip, 2008). Investigators
also investigated right-sided and bilateral treatment protocols for treatment of auditory hallu-
cinations (Lee et al., 2005). A series of recent studies explored optimizing stimulation param-
eters using brain imaging and neuronavigational tools (Schönfeldt-Lecuona et al., 2004;
Sommer et al., 2007; Hoffman et al., 2007; Montagne-Larmurier, Etard, Razafimandimby,
Morello, & Dollfus, 2009).
One notable finding in the literature on rTMS for schizophrenia is that therapeu-
tic amelioration of hallucinations appears to occur in some patients with short durations
of treatment. Preliminary data also suggest that therapeutic benefit may persist over time
and may recur when patients are retreated following symptom relapse (Fitzgerald, Benitez,
Daskalakis, De Castella, & Kulkarni, 2006).
Treatment of Chronic Pain
Motor Cortex Stimulation
Reflecting the recognition that chronic pain syndromes are likely to be associated with
changes in cortical activity (Seifert & Maihöfner, 2009), there has been increasing interest
in the use of rTMS approaches to modulate chronic pain. The main site for investigation
has been the primary motor cortex. Studies applying low-frequency stimulation to this site
have demonstrated modest and short-lasting pain reduction effects after single stimulation
sessions (Lefaucheur, Drouot, Keravel, & Nguyen, 2001; Pleger et al., 2004). Similar benefits
have been seen when stimulation was applied across multiple treatment sessions, for example,
analgesic effects seen in complex regional pain syndrome type 1 (Picarelli et al., 2010), but
negative studies have also been reported (Plow, Pascual-Leone, & Machado, 2012). Negative
studies have also been seen with the application of low-frequency rTMS (O’Connell, Wand,
Marston, Spencer, & Desouza, 2011). Antipain effects do appear to be dependent on the spe-
cific pain syndrome targeted, with facial pain, especially trigeminal neuralgia, appearing to
respond better than other types of pain syndromes (Plow, Pascual-Leone, & Machado, 2012).
A recent Cochrane review including 19 rTMS studies concluded that there was evidence for
short-term analgesic effects of single rTMS sessions, but there is limited evidence at this stage
of longer-term treatment benefit (O’Connell, Wand, Marston, Spencer, & Desouza, 2011).
DLPFC Stimulation
The second major treatment site that is gathering increasing attention is the DLPFC, as this
region of the brain may be involved in top-down regulation of pain perception. Initial studies
demonstrated that high-frequency stimulation applied to the left DLPFC could change percep-
tion of experimentally induced pain, and a similar effect could be produce with low-frequency
stimulation applied to the right DLPFC (Borckardt et al., 2007; Graff-Guerrero et al., 2005).
Subsequently, two initial studies have explored the utility of prefrontal stimulation in clinical
groups. An ongoing reduction in neuropathic pain was seen in a small trial of high-frequency
left DLPFC stimulation (Borckardt et al., 2009) and a similar benefit with right 1-Hz DLPFC
stimulation in patients with pain related to fibromyalgia (Sampson, Kung, McAlpine, &
Sandroni, 2011). There may be two significant advantages with the frontal approaches: ben-
efits appeared to persist past the end of the period of stimulation and it appears that unilateral
prefrontal stimulation has the potential to have bilateral therapeutic effects.
Treatment of Dementia
and Alzheimer’s Disease
TMS methods have attracted attention for their potential use both in understanding the
neurophysiology of dementing disorders as well as more recently in their potential treatment.
The greatest body of research has focused on the former, while therapeutic applications of
rTMS in dementing disorders have only just begun to be thoroughly explored. Early studies,
motivated by an intent to enhance cortical excitability with high-frequency rTMS, showed
that cognitive functions could potentially be improved with short periods of rTMS. For
example, a single session of prefrontal rTMS was shown to potentially moderate several pre-
frontal cognitive functions (Rektorova, Megova, Bares, & Rektor, 2005), and high-frequency
DLPFC rTMS was also shown to improve naming performance (Cotelli et al., 2006, 2008).
Interestingly, it seems that there is more capacity to enhance naming performance in a more
severely impaired group of patients, suggesting that therapeutic effects might be limited by
ceiling effects in less severely affected individuals.
More recently, several small studies have investigated whether longer periods of rTMS
could induce meaningful cognitive improvement. An improvement in language comprehen-
sion was demonstrated that persisted for up to 8 hours following a 4-week treatment proto-
col. Naming was not improved in this study (Cotelli et al., 2011). Beneficial effects persisting
to 3 months were seen in a second study (Ahmed, Darwish, Khedr, & Ali, 2012). In this trial,
prefrontal high-frequency rTMS applied sequentially to both hemispheres improved perfor-
mance across a number of rating measures, including the mini mental state examination, to a
greater degree than sham or low-frequency stimulation.
A new and interesting approach is to combine the provision of rTMS with specific
cognitive training. In a small pilot study, rTMS was applied across six brain regions identi-
fied on MRI scanning with patients also engaged in cognitive training that addressed tasks
relevant to these brain regions (Bentwich et al., 2011). Improvement was seen in a number of
patients, although a randomized evaluation of this approach is required.
Treatment of Stroke-Related Neurological

Impairment
Recently there has been considerable interest in the potential use of rTMS methods in the
rehabilitation of patients with stroke-related neurological impairment. Studies have primarily
focused separately on the potential rehabilitation of two forms of symptoms: motor and post
stroke aphasia. However, studies are also identifying the potential use of rTMS in other areas
of post stroke disability, such as in post stroke dysphagia (Park, Oh, Lee, Yeo, & Ryu, 2012).
Aphasia
Nonfluent aphasia is clearly a common persisting and significant disability that occurs fol-
lowing anterior left hemisphere strokes. The main rTMS approach explored to ameliorate
aphasia has used low-frequency stimulation targeted to the right inferior frontal gyrus, local-
ized to the right hemisphere homologue of the area affected by the stroke. This approach
has been suggested by neuroimaging studies that identified potentially excessive right hemi-
sphere activation, possibly as a result of a reduction of transcallosal input from the affected
left hemisphere structures (Naeser et al., 2012). The therapeutic potential of this approach
was explored across a number of studies and case reports (Turkeltaub et al., 2012; Barwood
et al., 2011; Hamilton et al., 2010). Several reports have suggested that stereotactic localiza-
tion of the stimulation site enhances response to this form of treatment by adequately iden-
tifying the appropriately hyperactive region in the right hemisphere (Naeser et al., 2012).
Ongoing research is required to establish whether short-term benefits persist over time and
translate into improved functional outcomes.
Motor Impairment
A number of studies have investigated the modulation of motor symptoms resulting from
stroke using rTMS, with stimulation focused on the primary motor cortex. As with the
aphasia research described above, these studies included trials providing low-frequency
stimulation to the unaffected hemisphere opposite to the site of the stroke lesion (Khedr,
Abdel-Fadeil, Farghali, & Qaid, 2009; Takeuchi et al., 2008). In addition, a series of studies
directly targeted the affected hemisphere, typically with high-frequency stimulation aimed at
enhancing cortical activity at the site of injury. The outcomes of these studies are summarized
in several recent and detailed reviews (Corti, Patten, & Triggs, 2012; Khedr & Fetoh, 2010).
One recent metaanalysis found that there was a moderate effect size (0.55) for improving
motor outcomes across a series of 18 studies, including a total of 392 patients (Hsu, Cheng,
Liao, Lee, & Lin, 2012). Greater effects were seen in patients with subcortical strokes and
in studies where low-frequency stimulation was applied to the hemisphere contralateral to
the stroke lesion. Importantly, across rTMS studies in stroke, few substantive adverse events
have been reported, despite the fact that some of these treatments were targeted to areas
in which there are clearly pathological cortical changes. Larger studies are now required to
establish the role of rTMS post stroke and to explore novel stimulation approaches, such
as TBS, that have recently been identified as having therapeutic potential (Meehan, Dao,
Linsdell, & Boyd, 2011).
Treatment of Parkinson Disease

Parkinson disease is a disorder in which the motor cortex would appear to be a relatively
obvious target for rTMS treatment. Degeneration of dopaminergic nuclei disrupts motor
performance, and it is proposed that, in part, this occurs due to reduction of inputs to
the frontal (including motor) cortex (Lefaucheur et al., 2004). Soon after the develop-
ment of rTMS methods, high-frequency stimulation was applied over the motor cortex to
try to modulate movement variables (Pascual-Leone et al., 1994). These researchers found
that a single session of 5Hz stimulation applied to the motor cortex could improve reac-
tion and movement times in patients but not those who are healthy. Since that time, a
series of studies have evaluated rTMS methods in Parkinson disease, but unfortunately the
methodology across trials has been highly divergent. Studies have evaluated both low- and
high-frequency stimulation, the use of focal and nonfocal coils, and, more recently, out-
comes across both motor and nonmotor brain regions. A recent metaanalysis pooled the
outcomes from 10 trials, including 6 single-session and 4 multisession (6 to 10 treatment
days) protocols. There was an overall benefit of active over sham stimulation, with an effect
size of 0.55 in the seven studies that used high-frequency stimulation (Elahi, Elahi, &
Chen, 2009). No clear benefit was seen in low-frequency stimulation studies. However,
the high-frequency stimulation trials included three in which stimulation was applied to
the motor cortex and four in which it was applied to prefrontal brain regions, confounding
interpretation of this finding.
The notion of stimulating DLPFC in Parkinson disease arose from observations that
DLPFC stimulation targeting depressive symptoms also improved motor function (Fregni,
et al., 2004) and that prefrontal stimulation could change subcortical dopamine release
(Strafella, Paus, Barrett, & Dagher, 2001). Unfortunately, although positive effects have been
seen in some studies, these have not been consistent across all trials and no substantive multisite
trials have evaluated rTMS methods in Parkinson’s disease to date. Novel approaches such as
TBS (Benninger et al., 2011) and combining rTMS with rehabilitations or training methods
(Yang et al., 2013) have been investigated in initial studies but require more detailed evaluation.
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10
Development of Other
Neurostimulation Interventions
Colleen Loo, Scott Aaronson, and Paul E. Holtzheimer
Introduction
Psychotropic medications and psychotherapy are effective for many patients with psychi-
atric disorders. However, a substantial number of patients either fail to achieve or fail to
sustain full remission with these treatments. Alternative interventions, especially for those
patients who do not respond to or tolerate standard treatments, include a variety of neuro-
stimulation approaches. Electroconvulsive therapy (ECT) predated antidepressant and anti-
psychotic medications by nearly two decades (Lisanby, 2007) and remains one of the most
effective treatments in psychiatry. More recently, a number of other neurostimulation tech-
niques have been investigated for the treatment of patients with neuropsychiatric disorders.
These include repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy
(MST), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and
deep brain stimulation (DBS). These interventions vary significantly in terms of method for
stimulating neural tissue, initial mechanism of action, and patient populations most likely to
respond. This chapter reviews the various neurostimulation interventions either in use or in
active development for the treatment of patients with psychiatric disorders.
ECT
Overview and Efficacy
ECT is a widely recommended treatment for depression that is pharmacotherapy resistant
or where there is clinical urgency for rapid improvement (American Psychiatric Association,
2001; Lancet, 2003; NICE Clinical Guidelines, 2009). ECT has been shown to have superior
efficacy to pharmacotherapy in depression (Lancet, 2003; Kho, van Vreeswijk, Simpson, &
Zwinderman, 2003). Where dose treatment levels are adequate (e.g., excluding low-dose uni-
lateral ECT), remission rates range from 55% to 87% in research samples (Kellner et al.,
Development of O t h e r N e u r o s t i m u l at i o n I n t e r v e n t i o n s | 137
2010; Petrides et al., 2001; Sackeim et al., 2000; Sackeim et al., 2008) and from 40% to
68% in community samples (Kho, Zwinderman, & Blansjaar, 2005; Prudic, Olfson, Marcus,
Fuller, & Sackeim, 2004). The majority of patients in these samples were treatment resistant,
having failed several trials (i.e., at least one adequate trial) of antidepressant medication in
the current episode (Table 10.1).
ECT is effective in treating bipolar depression, which may respond more quickly than
unipolar depression (Daly et al., 2001; Sienaert, Vansteelandt, Demyttenaere, & Peuskens,
2009b), though switching into mania may occur (Loo, Katalinic, Mitchell, & Greenberg,
2011). ECT has efficacy in treating acute psychotic symptoms in schizophrenia and may
enhance outcomes when combined with antipsychotic medications (Tharyan & Adams,
2005). ECT is at least as effective as pharmacotherapy in treating acute mania (Loo et al.,
2011). It is a highly and rapidly effective treatment for catatonia (Fink, 2001; Gazdag,
Ungvari, & Caroff, 2009). Predictors of response to ECT in depression include older age,
psychotic features, and lower treatment resistance (de Vreede, Burger, & van Vliet, 2005;
Dombrovski et al., 2005; Petrides et al., 2001).
Side Effects and Tolerability

Cognitive side effects are common after ECT and are often time limited (with recovery in
the range of weeks to months after a course of ECT). However, persistent retrograde amne-
sia may occur, the risk being highest with bitemporal ECT (Sackeim et al., 2007). A meta-
analysis found that by 15 days after the end of treatment, cognitive function tended to be
improved compared with pre-ECT levels, reflecting improved mental state from the treat-
ment (Semkovska & McLoughlin, 2010). The treatment technique used in ECT (e.g., elec-
trode placement, stimulus parameters, pulse width) is an important determinant of the extent
and persistence of cognitive side effects (Sackeim et al., 2007). Newer treatment approaches
such as reduction of the stimulus pulse width to the “ultrabrief ” range (0.3 ms) result in
less cognitive disturbance than the brief pulse (1.0–1.5 ms) treatment approach currently
TABLE 10.1 Overview of Key Features of rTMS and Other Brain Stimulation

Therapies
Treatment Efficacy Side Effects Anaesthesia Time to Response Cost
rTMS Effective in mild to Scalp pain, headache No 4–8 weeks +

moderate TRD
tDCS Effective in mild to Skin redness, tingling No 4–8 weeks +
moderate TRD
ECT Effective in moderate Cognitive side effects. Yes, general 2–4 weeks ++
to high TRD Risks anaesthesia
MST Effective in moderate Risks anaesthesia Yes, general 2–4 weeks ++
to high (?) TRD
VNS Effective in high TRD Intermittent hoarseness Yes, local 3–24 months +++
or coughing
DBS Effective in high TRD Infection, bleeding, Yes, general/ 3–24 months ++++
target dependent local
neurospychiatric symptoms
+ low cost; ++ moderate cost; +++, ++++ high cost.

in common use (Loo, Sainsbury, Sheehan, & Lyndon, 2008; Sackeim et al., 2008; Sienaert,
Vansteelandt, Demyttenaere, & Peuskens, 2010).
Speed of Response and Maintenance Effects

Acute response to ECT is typically rapid, with up to 90% of depressed patients attaining
remission within nine treatments over a 3-week period (Kellner et al., 2010). However, thera-
peutic gains may rapidly recede within the first few weeks if the ECT course is ceased abruptly
(Prudic et al., 2004, 2013), and relapse rates may be as high as 84% over the next 6 months in
the absence of any continuation and maintenance treatment (Sackeim, Haskett, et al., 2001).
This relapse rate is reduced by optimal pharmacotherapy (Sackeim, Haskett, et al., 2001) and
the use of continuation and maintenance ECT (Kellner et al., 2006; Prudic et al., 2013).
ECT versus rTMS
A few studies have directly compared the efficacy of ECT and rTMS in depression. Though
participants were randomized to receive ECT or rTMS, these studies were not double-blinded
due to ethical constraints against the use of sham ECT (with anesthesia). A metaanalysis of
these studies found the efficacy of ECT to be superior (Slotema et al., 2011), the difference
corresponding to a weighted effect size of 0.47. An open-label pilot study suggested that the
superior efficacy of ECT might be particularly evident in psychotic depression (Grunhaus
et al., 2000). There is little controversy over superior cognitive outcomes with rTMS (which
does not cause cognitive impairment; Moreines, McClintock, & Holtzheimer, 2011) as com-
pared to ECT. There are criticisms of the treatment approach used in these studies for both
modalities of treatment including fixed parameters and number of treatments for TMS as well
as the potential inadequate dosing of unilateral ECT. Nevertheless, the evidence to date clearly
indicates that ECT has superior efficacy, both in speed of response and overall response rates.
Conclusion
ECT remains the most effective proven treatment for depression in widespread clinical use.
Response and remission rates are high, and treatment effects occur rapidly, typically within
2–3 weeks. The main limitations of its use are the risk of cognitive side effects, the require-
ment for general anesthesia, and stigma.
MST
Overview
MST is similar to ECT in that it provides a series of treatments, each involving induction
of a seizure, over several weeks. MST uses a TMS device to induce seizure; similar to ECT,
general anesthesia is used to minimize side effects. The rationale for MST is based on data
that suggest that more focal seizure induction in ECT is associated with fewer cognitive
side effects (Lisanby, 2007; Sackeim et al., 2008). MST provides a highly focused electrical
induction of a generalized seizure, suggesting that it will have efficacy similar to that of ECT
but with fewer cognitive side effects (Lisanby, Luber, Finck, Schroeder, & Sackeim, 2001).
The risks and potential side effects of MST are similar to those associated with ECT, as both
involve seizure induction under general anesthesia.
Efficacy and Safety
In several studies, MST has been shown to have a superior cognitive safety profile compared
to ECT (Kayser, Bewernick, Axmacher, & Schlaepfer, 2008; Kayser et al., 2011; Kosel,
Frick, Lisanby, Fisch, & Schlaepfer, 2003; Lisanby, Luber, Schlaepfer, & Sackeim, 2003;
White et al., 2006). An initial controlled trial of MST versus ECT for depression found
that ECT was more efficacious (White et al., 2006), but MST required lower doses of anes-
thetic agents. Another small controlled trial found similar antidepressant effects for MST
and ECT. However, recovery of orientation was faster in the MST patients, suggesting that
MST may be associated with fewer long-term cognitive side effects (Kayser et al., 2011). An
open-label study of high-dose (100 Hz) MST in depressed patients found significant antide-
pressant effects associated with treatment and no adverse cognitive effects (Fitzgerald et al.,
2013). Although the efficacy of MST to date is either similar or inferior to ECT, it is noted
that earlier studies often treated at or near seizure threshold. Since more focal induction of
a seizure may require higher subsequent treatment parameters (e.g., five to eight times the
seizure threshold for right unilateral ECT), it is likely that MST needs to stimulate at several
times the seizure threshold in order to be most effective. Newer devices allow this capability,
and data from large-scale clinical trials are awaited.
tDCS
Overview
tDCS is a noninvasive technique in which a weak direct electrical current is passed across the
scalp. The current flows in one direction (hence “direct” in contrast to an alternating current,
which is bidirectional, as in ECT) from the anodal electrode to the cathodal electrode. tDCS
can lead to changes in the excitability of neurons in stimulated cortical regions. The stimula-
tion is subconvulsive and given without any need for anesthesia. Weak electrical stimulation
has been applied in animal models and humans for many decades and was previously known
as “brain polarization.” Animal experiments and neurophysiological studies in humans have
shown that anodal stimulation depolarizes the neuronal membrane, whereas cathodal stimu-
lation results in hyperpolarization (Bindman, Lippold, & Redfearn, 1964; Nitsche & Paulus,
2000). More recently, the term “tDCS” has been used to refer to stimulation given with
modern, reliable equipment with the potential to deliver higher stimulus intensities (1–3
mA, compared with <1 mA previously). Lasting effects (up to 90 minutes) on neuronal func-
tion after a single session of stimulation have been demonstrated (Nitsche & Paulus, 2000).
Studies probing the mechanisms of action of tDCS have identified both membrane and syn-
aptic processes (Arul-Anandam & Loo, 2009).
tDCS has been investigated for the treatment of neuropsychiatric disorders, includ-
ing poststroke rehabilitation (Nitsche et al., 2008) as well as cognitive enhancement
(Fox, 2011). In therapeutic applications, treatment sessions are typically repeated on con-
secutive weekdays over a number of weeks, with empirical data showing cumulative changes
in cortical excitability with successive daily sessions (Alonzo, Brassil, Taylor, Martin, & Loo,
2012). From studies to date, the time course for treatment and onset of effects appear to be
similar to those of rTMS.
Efficacy in Depression and Other Disorders

Clinical trials in psychiatry have focused initially on the treatment of depression, with
the majority of trials using tDCS technology (since 2000) and reporting positive results.
A metaanalysis of the first six randomized, sham-controlled trials (RCTs) post 2000 con-
cluded that tDCS had antidepressant efficacy (effect size of 7.4), though a subsequent
metaanalysis of response rates (rather than mean change in depression scores) failed to find
a difference between active and sham treatment (Berlim, Van den Eynde, & Daskalakis,
2013). Participants enrolled in these trials ranged from being nontreatment resistant
to highly treatment resistant, including having failed ECT. Of the two largest RCTs in
depression, Loo et al. (2012) reported a 13% response rate after 3 weeks of tDCS in par-
ticipants who had failed, on average, two adequate trials of antidepressants (though the
response rate increased to 50% after open-label extension to 6 weeks of treatment). In a
less treatment-resistant and nonmedicated sample, Brunoni et al. (2013) reported a 43%
response rate after 12 sessions of tDCS spaced over 6 weeks (10 sessions over 2 weeks, then 2
additional sessions at fortnightly intervals), with a higher response rate of 63% when tDCS
was given in combination with sertraline. Of interest, in this study, which tested the four
possible combinations of tDCS or sham stimulation with sertraline or placebo medication,
the response to tDCS monotherapy (43%) was higher than the response to monotherapy
with sertraline 50 mg (33%). However, inadequate dosing may have contributed to a low
response rate in the latter group. Apart from this, there are no data directly comparing the
efficacy of tDCS with other antidepressant treatments (including rTMS and ECT).
There is open-label evidence that tDCS may also be effective in bipolar depression
(Brunoni et al., 2011), and sham-controlled RCTs of tDCS in bipolar depression are cur-
rently in progress. Recently, a sham-controlled RCT found that tDCS reduced the severity
of auditory hallucinations in schizophrenia (Brunelin et al., 2012).
Safety and Tolerability

In the above studies, tDCS was safe with only minor side effects (most commonly transient
skin redness and tingling), though careful attention to treatment technique is necessary, as
skin burns may occur if the skin–electrode contact is suboptimal (Loo et al., 2011). Studies
suggest that tDCS may actually improve cognitive functioning in the period immediately
after stimulation, including data from double-blind, sham-controlled trials in depressed
participants (Loo et al., 2012). There are data to suggest that anticonvulsants, which alter
ion-channel permeability (e.g., carbamazepine), and benzodiazepines may reduce the effec-
tiveness of tDCS (Brunoni et al., 2012; Nitsche et al., 2003, 2004).
Conclusion
The efficacy and safety profile of tDCS show promise, with early evidence suggesting it
may have antidepressant effects that are similar to those of rTMS. However, more studies
are needed to confirm efficacy and safety in depression and to investigate its role in treat-
ing other psychiatric disorders. tDCS involves inexpensive and portable equipment, which
would facilitate large-scale clinical translation. Lack of cognitive impairment and short-term
enhancement of cognitive function may be added advantages of treatment.
VNS
Overview of Implantable Devices
In the growing universe of neurostimulation techniques, the implantable devices VNS and
DBS are in a unique position. From several standpoints, the paradigm of treatment differs
dramatically from all other mental health treatment strategies. This is because of the high cost
(approximately $35,000 for VNS and $250,000 for DBS), the surgically invasive nature of
the procedure, the target population of the most treatment-refractory patients, and a cumu-
lative response pattern, which grows over months and years rather than weeks. The above
necessitate a shift in how we study these devices and how we incorporate them into clinical
care. We need to create new research instruments or new perspectives as to what constitutes
a treatment response on existing scales (perhaps the standard 50% drop in depression rating
scale score as a marker for response is too high a barrier for these persistently ill patients).
Also, when the time to see significant response is 6 months or longer, sham-controlled
blinded studies may be ethically inadvisable.
Overview of VNS
VNS was first developed and approved by the US Food and Drug Administration (FDA) in
1997 for the treatment of intractable epilepsy. Observations made by investigators and clini-
cians supported the notion of mood improvement in implanted seizure patients (Elger, Hoppe,
Falkai, Rush, & Elger, 2000; Harden et al., 2000). This led to a series of studies in patients with
treatment-resistant depression (TRD) and eventual clearance by the FDA for use in depression
when at least four treatments had failed (Aaronson et al., 2012; Rush, Marangell, et al., 2005;
Sackeim, Rush, et al., 2001). The current FDA-approved device (Cyberonics, Inc., Houston,
Texas, US) consists of a titanium-encased lithium battery that is implanted under the skin in
the upper chest wall. The battery is connected by a lead wire that is tunneled under the skin to
pig-tailed electrodes wrapped around the left vagus nerve. The device is implanted using two
incisions under general or local anesthesia in 1 to 2 hours. Two weeks following the surgery,
the device is activated and stimulation parameters are set by a wand connected to a handheld
programming device. The telemetric programming wand sets the following four stimulation
parameters for the device: the current (0.25–3.0 mA), the frequency of stimulation (20–50 Hz),
the pulse width (130–500 ms), and the duty cycle (adjustable from the usual settings of 30 sec-
onds on and 5 minutes off ). The initial settings are gradually titrated up, usually over the first
2 weeks of treatment as tolerated by the patient. While the mechanism of action is not clear,
several animal studies and human neuroimaging studies demonstrate increased limbic activity
and changes in neurochemistry after chronic treatment (Carpenter et al., 2004; Conway et al.,
2013; Krahl, Senanayake, Pekary, & Sattin, 2004; Neuhaus et al., 2007). VNS demonstrates
gradually improving efficacy, which starts about 6 months into treatment and grows over time.
Studies have shown improving outcomes at 1 and 2 years (Bajbouj et al., 2010; Nahas et al.,
2005; Nierenberg, Alpert, Gardner-Schuster, Seay, & Mischoulon, 2008).
Efficacy of VNS in TRD
VNS has been studied in highly treatment-resistant populations. The first open-label studies
comprised a total of 60 patients including both unipolar and bipolar depression (Rush et al.,
2000; Sackeim, Rush, et al., 2001). The average number of adequate failed antidepressant
trials in these studies was at least two and averaged between four and five. Response rates at
10 to 12 weeks were between 30% and 40% and remission rates were 14%–17%. Remarkably,
naturalistic long-term follow-up on these patients showed continued improvement at 1 and
2 years of chronic treatment with response rates at 44% and 42% and remission rates at 27%
and 22%, respectively (Aaronson et al., 2012; Nahas et al., 2005; Rush, Sackeim, et al., 2005).
A subsequent VNS trial was a randomized trial with 235 patients that included
a 12-week sham-controlled phase followed by a long-term observational phase (Rush,
Marangell, et al., 2005). Patients enrolled in this study had a higher level of treatment resis-
tance, having failed at least four antidepressant trials inclusive of monotherapy and adjunc-
tive agents. At the end of the 12-week sham treatment, there was no significant difference
between sham and active treatment groups (15% active versus 10% sham response rates).
Follow-up observations again demonstrated a cumulative improvement in response and
remission, with response rates between 27% and 34% depending on outcome measure and a
remission rate of 16% at 1 year (Rush, Sackeim, et al., 2005). Also, longer-term data support
a decline in suicide attempts and psychiatric hospitalizations for depression in patients with
VNS compared to patients on medications alone.
A recently published VNS dose-finding study compared three levels as follows: low
(0.25 mA and 130-ms pulse width), med (1.0 mA and 250-ms pulse width), and high (1.5
mA and 250-ms pulse width) of double-blinded stimulation in 331 highly treatment-resistant
patients (Aaronson et al., 2012). More than 97% had failed at least six previous treatments.
Acute-phase treatment lasted 22 weeks, after which output current could be increased by up
to 0.75 mA and follow-up was done for up to 50 weeks. While the treatment arms did not
show significant separation at 22 weeks, all groups showed significant improvement on the
primary outcome measure (a clinician-rated inventory of depressive symptoms [IDS-C]).
In the long-term phase, mean change in IDS-C scores showed continued improvement. An
analysis of acute-phase responders demonstrated significantly greater durability of response
at the med and high doses than at the low dose. At 22 weeks, overall response rates were 20%
and remission rates were 10%. At 50 weeks, overall response rates varied from 27% to 53%,
depending on the scale and the assigned group, and remission rates ranged from 15% to 23%.
The percent of acute-phase responders who continued to respond at 50 weeks varied from
77% to 92% of the med- and high-dose groups compared to 44%–69% of the low-dose group.
Side Effects and Tolerability

There is a large safety-related database given that the majority of VNS implantations are for
control of seizures. The device is well tolerated and the retention of patients through these
studies has been very high. The major adverse events are related to the surgery for implanta-
tion, which are self-limited or associated with the stimulation part of the duty cycle. The
electrode for the VNS is typically wrapped around the left vagus nerve near the superior and
recurrent laryngeal nerves. During stimulation, this can cause voice alterations, hoarseness,
or coughing, which are all frequently seen. Bradyarrhythmias and sleep apnea are rare. The
rate of stimulation-induced mania or hypomania is low, and adjustment of treatment param-
eters is likely to reduce symptoms.
Conclusion
Despite evidence that VNS can be an effective treatment for patients who have failed many
adequate medication trials, several difficulties have plagued the development of VNS as a
therapy for TRD and hampered large research trials. It takes at least 6 months, possibly more,
to see antidepressant effects. As the first major VNS trial had 12 weeks from implantation
as its primary outcome measure point, the double-blind phase was likely insufficiently long
to demonstrate significant separation. Even the longer 22-week dose-finding study may have
been of insufficient length. A question can be raised from an ethical standpoint as to how
long should seriously ill patients be treated within a sham-controlled study.
Another complication seen in the dose-finding study is that the low-dose arm (0.25
mA and 125-ms pulse width) was intended to be a surrogate for sham treatment. As it
turned out, even this low-dose arm demonstrated significant response compared to the
in-group baseline. Thus, primary outcome measures were not met, though patients treated
with the low dose had a significantly less durable response than higher-dose groups. This
inability to meet primary outcome measures in two large studies has given third-party
payers an excuse to deny coverage despite FDA clearance of VNS for use in the severe TRD
population.
DBS
Overview
DBS is an established treatment option for patients with severe, medication-resistant movement
disorders (e.g., Parkinson disease, essential tremor, dystonia). DBS of the ventral anterior inter-
nal capsule and ventral striatum (VC/VS) has been approved through a Humanitarian Device
Exemption from the FDA for the treatment of severe treatment-refractory obsessive-compulsive
disorder (OCD; Greenberg et al., 2010). With DBS, one or more electrodes (typically with
several individual contacts per electrode) are implanted into a specific brain region using stereo-
tactic neurosurgical techniques. These electrodes are connected to a subcutaneous computer/
battery pack (also called an implantable pulse generator [IPG]) through wires that run under
the skin from the scalp to the IPG location. The most significant potential adverse events asso-
ciated with DBS are related to implantation surgery (bleeding, infection, complications from
anesthesia). Other adverse events are typically related to specific effects based on the target for
stimulation. DBS likely operates through modulation of activity within a broad network of
brain regions involved in regulation of a specific behavioral system.
Efficacy and Safety of DBS with Different

Target Sites
Several studies have tested the safety and efficacy of DBS for TRD. A variety of brain tar-
gets have been explored. Individual studies have universally been small (up to 20 patients),
uncontrolled, and open label (for long-term effects). However, the patients included repre-
sent those who are the most treatment resistant; most studies have included patients with
chronic depression (often with a current depressive episode lasting an average of 4 or more
years) that have failed a large number of treatments in the current episode (an average of
six to seven medications, electroconvulsive therapy, and psychotherapy). Nearly all patients
included have become disabled due to their depression.
The DBS target with the earliest published data for use in TRD patients is the sub-
callosal cingulate white matter (SCCwm). Choice of this target was based on a converging
database that implicated this region in the neurobiology of the antidepressant response and
TRD (Mayberg, 2009). With chronic SCCwm DBS up to several years, remission rates have
been shown to be approximately 40%–60% (Guinjoan et al., 2010; Holtzheimer et al., 2012;
Kennedy et al., 2011; Lozano et al., 2008; Mayberg et al., 2005; Puigdemont et al., 2011).
Those with depression in the context of bipolar disorder may respond as well as those in the
context of major depressive disorder (Holtzheimer et al., 2012). Depressive relapse has been
uncommon among remitters. No adverse effects of acute or chronic SCCwm DBS have been
identified, including no neurocognitive impairments (Holtzheimer et al., 2012; McNeely,
Mayberg, Lozano, & Kennedy, 2008).
Other trials have demonstrated efficacy for DBS of the VC/VS target previously used
for OCD. Choice of this target was based on the antidepressant effects seen in OCD patients
receiving stimulation at this target (Malone et al., 2009). A similar but smaller target has
been the nucleus accumbens, which makes up a significant portion of the ventral striatum
(Bewernick et al., 2010; Bewernick, Kayser, Sturm, & Schlaepfer, 2012). An additional ratio-
nale for this target was its role in reward processing and potentially anhedonia, which is
a prominent symptom in the depressive syndrome (Schlaepfer et al., 2008). Efficacy with
each of these DBS targets was similar to that seen with SCCwm DBS. With both of these
targets, acute stimulation was associated with a number of side effects, including hypomania
(a mild degree of mania), anxiety, perseverative speech (the persistent repetition of a word or
phrase), autonomic symptoms, and involuntary facial movements. These effects were revers-
ible with changes in stimulation parameters, and there were no adverse effects of chronic
DBS, including no neuropsychological impairments.
The median forebrain bundle (MFB) is a collection of ascending and descending white
matter fibers that connect the midbrain and ventral striatum. Based on its presumed role
in reward processing as well as connection to other potential targets for DBS for TRD, it
was hypothesized that bilateral stimulation of the MFB would have antidepressant efficacy
in patients with TRD (Coenen, Panksepp, Hurwitz, Urbach, & Madler, 2012; Schlaepfer,
Bewernick, Kayser, Madler, & Coenen, 2013). An initial report of MFB DBS for TRD
described clinical response in six of seven patients with at least 12 weeks of open-label stimu-
lation, with four patients achieving remission (Schlaepfer et al., 2013). A number of adverse
events were noted, including vision/eye movement changes in all seven patients (related to
specific stimulation parameters). No cognitive impairments were noted over the 3 months
of stimulation.
Case reports have described antidepressant efficacy for DBS of the inferior thalamic
peduncle ( Jimenez et al., 2005) and habenula (Sartorius et al., 2010). The rationale for the
inferior thalamic peduncle target included its role in the thalamo-cortical network likely
involved in mood regulation. The habenula target was chosen based on its role in monoami-
nergic neurotransmission, especially to prefrontal cortex.
Conclusion
DBS shows early promise as a potential treatment for TRD. However, caution is advised
because data to date are based on small open-label trials. These encouraging but prelimi-
nary data will need validation in large, randomized, controlled trials. Ideally, these studies
will include appropriate sham-controlled designs. As with VNS, the antidepressant effects of
DBS appear to take several weeks to months to become apparent. This again raises the ethical
and scientific questions of what an appropriate sham-controlled study duration should be.
What Is the Role of rTMS Relative to the

Above Brain Stimulation Therapies?
Key factors to consider when choosing the most appropriate brain stimulation treatment
are the level of the patient’s treatment resistance and the relative efficacy of the treatments,
predictors of response, clinical urgency and risk, feasibility, tolerability and safety of the
treatments, patient preference, and type of depression (bipolar, melancholic, psychotic, cata-
tonic features). At the time of writing (2013), only ECT, rTMS, and VNS are considered
FDA-approved treatments for depression. However, the potential roles for MST, tDCS, and
DBS are discussed here in light of the research evidence available to date.
Depression
For moderately depressed patients who are not significantly treatment refractory and not
at immediate clinical risk (such that a rapid response is a priority), rTMS would be the
preferred nonpharmacologic somatic treatment. It is nonconvulsive, does not require gen-
eral anesthesia or a surgical procedure, and is safe and well tolerated. tDCS may also be an
option, as evidence to date suggests the time course of treatment and efficacy outcomes are
similar to those of rTMS, with arguably a superior safety profile (i.e., no risk of accidental
seizures). For patients who are moderately treatment resistant (e.g., have failed one to two
adequate courses of pharmacotherapy), appropriate treatment options would be rTMS (or
tDCS) and ECT (or MST). The choice of treatment should take into account the severity
of the illness, clinical urgency, physical risks (e.g., risk of accidental seizure with rTMS, risk
from anesthesia with ECT and MST), and patient preference. ECT is more efficacious than
rTMS, induces improvement more quickly, and carries a higher likelihood of full clinical
response. This has to be weighed against the higher likelihood of cognitive side effects with
ECT, though the risk varies widely with the form of ECT used. MST is likely to have a treat-
ment role in this group, as preliminary studies suggest it may have efficacy that is compa-
rable to that of weaker forms of ECT, with minimal cognitive side effects. Likewise, tDCS
may have a role akin to that of rTMS in this group. For more highly treatment-resistant
patients (e.g., those who have failed four or more antidepressant treatments, including any
trials of rTMS or tDCS), the treatment of choice would be ECT (or MST), VNS, and
possibly DBS
Patients who are depressed with psychotic or catatonic features should be given
ECT rather than rTMS, as there is insufficient evidence for the efficacy of rTMS in severe
depression characterized by psychosis and/or catatonia. Speed of response is an important

consideration. In situations of clinical urgency (e.g., high suicide risk, poor oral intake due to
severe depression, catatonia, psychotic symptoms), the treatment of choice would be ECT
rather than TMS, tDCS, MST, VNS, or DBS.
In patients with extreme TRD who have failed to respond to an adequate trial of ECT,
it is unlikely that TMS, tDCS, or MST would be effective. Appropriate treatment options
would then be VNS or DBS. Thus, patients who have failed to respond to antidepressant
medications (and/or rTMS, tDCS, or MST) should next be offered ECT. If this treatment
fails, VNS or DBS could be considered.
For patients successfully treated with ECT who tend to relapse into depression despite
adequate pharmacotherapy, maintenance ECT in combination with medications has been
shown to reduce the risk of relapse. Likewise, there may be a role for maintenance rTMS in
patients who have responded to an acute course of rTMS but who relapse with medication
prophylaxis alone. The optimal schedule for maintenance rTMS sessions and the patients
most likely to benefit need to be clarified by further research. Whether rTMS has a role sub-
stituting for maintenance ECT is unclear (Figure 10.1).
Depression—non-treatment resistant/
treatment resistant
Medication
TMS or tDCS* Severely ill, more highly
treatment resistant, clinically
urgent, psychotic, catatonic
fail to respond
ECT
or MST*
fail to respond
VNS DBS*
fail to respond
*Currently an experimental treatment for depression.
F I GUR E 10 .1 Flowchart showing the role of rTMS and other therapies in the treatment of depression.
Schizophrenia and Other Disorders

Efficacy has been demonstrated for rTMS in treating auditory hallucinations in schizophre-
nia, though its effects on other features of the disease are less clear (Matheson, Green, Loo, &
Carr, 2010). Thus, for patients with schizophrenia where persistent auditory hallucinations
despite treatment with antipsychotic medications are prominent and problematic, a trial of
rTMS should be considered. If the problem is of more general acute psychotic symptoms
despite treatment with antipsychotic medications, it would be more appropriate to consider
ECT rather than rTMS. At present, there are insufficient data to recommend the clinical use
of tDCS, MST, VNS, or DBS in schizophrenia.
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11
Limitations of Transcranial
Magnetic Stimulation and
Future Directions for Clinical
Research
Sarah H. Lisanby
Introduction
Transcranial magnetic stimulation (TMS) represents a paradigm shift for clinical psychia-
try. Never before have clinicians been able to focally target the neurocircuitry that underlies
brain-based disorders noninvasively. Now our models for the pathophysiology of psychiatric
disorders can be tested via an intervention that can both test hypotheses about neurocircuitry
as well as deliver therapy that changes the functioning of that circuitry in a lasting fashion.
TMS offers the unprecedented promise of moving beyond what psychotherapy and
psychopharmacology can do for patients and providing an effective alternative when these
other interventions are unsuccessful or cannot be tolerated due to side effects. It also offers
the compelling promise of circuit-guided treatment, by which one can leverage advances in
neuroscience regarding the distributed networks underlying the disorder and use these as
targets to refine the application of an intervention to correct abnormal functioning in these
network. Such an approach offers the dual features of being focused on the underlying neu-
rocircuitry as well as representing a means of tailoring the focus to each individual.
As exciting as these developments are for our field, there remain certain limitations to
the present-day practice of clinical TMS in neuropsychiatry. These limitations can be cat-
egorized as those relating to the efficacy of TMS (including its therapeutic potency, thera-
peutic spectrum, approaches to patient selection, and individualization of the treatment),
the safety of TMS (including seizure risk and safety in special populations), and clinical
trial design/methodologies (including valid sham conditions, effective masking, auditory
L i m i tat i o n s of T r a n s c r a n i a l M ag n e t i c S t i m u l at i o n | 153
and somatosensory confounds, and reporting of parameters and procedures to enable valid
replication).
In this chapter we review those limitations, present them in the context of the historical
development of the first neuromodulation treatment in psychiatry (electroconvulsive ther-
apy [ECT]), and highlight future directions to address those limitations. ECT technique
has undergone significant evolution over its seven decades of use. Likewise, we expect TMS
technique to evolve with time and lead to future refinements in the technology and its clini-
cal application.
Limitations to the Efficacy of Clinical TMS

Potency, Speed of Response,
and Maintenance Treatment
The antidepressant efficacy of TMS, while statistically significant and supported by multiple
metaanalyses, is modest and is widely considered to be less effective than the gold standard
ECT. The overall effect size of TMS in the pivotal trial sponsored by the manufacturer was
0.55 (confidence interval [CI], 0.10–1.00), which is considered a moderate effect. A key
predictor of response was the number of failed adequate antidepressant trials in the current
episode. Effect size was 0.83 (CI, 0.20–1.48) for those patients with a single adequate medi-
cation trial failure in the current episode and 0.42 (CI, −0.30–1.15) in those patients with
more than one adequate medication failure in the current episode (Lisanby et al., 2009).
However, it is the more medication-resistant patients who are in the most need of safe and
effective alternatives and for whom ECT remains the treatment of choice. The current US
Food and Drug Administration (FDA)-labeled indication for TMS is limited to this subset
of the depression population with a single failed adequate trial in the current episode. To have
a greater clinical impact, broadening this narrow therapeutic spectrum will be important, so
that patients who are in the most need of safe and effective alternatives will have options.
Randomized controlled trials and metaanalyses support a higher observed acute
response rate with ECT than with TMS (though it is acknowledged that such trials cannot
mask the patient-to-treatment condition because one involves anesthesia and seizure induc-
tion with the attendant side effects while the other does not; Eranti et al., 2007; Hansen
et al., 2011; Keshtkar, Ghanizadeh, & Firoozabadi, 2011; McLoughlin et al., 2007). Studies
also report ECT as being more cost effective than TMS (Knapp et al., 2008).
Furthermore, despite descriptions of rapid response after 1 or 2 weeks of treatment
in early studies, larger trials support a speed of action that more closely mimics antidepres-
sant medications, with optimal response at 6 weeks (George et al., 2010; O’Reardon et al.,
2007). This makes TMS less effective and slower acting than ECT, albeit with a superior
safety profile.
Lacking at present is deep knowledge about how best to maintain remission follow-
ing effective treatment with TMS. Durability of response following remission from TMS
appears to be robust (Mantovani et al., 2012), but knowledge of optimal relapse prevention
strategies and maintenance TMS schedules is limited.
Methods to Inform Patient Selection

and Personalize the Intervention
As with other treatments in psychiatry and the rest of medicine, therapeutic response to
TMS is variable. Aside from history of medication resistance, other factors have been identi-
fied as contributing to response, such as age, duration of illness, and comorbidity. Lacking
at present is knowledge of how to select patients most likely to respond to TMS and how
to personalize the intervention to optimize their response. Given the focality of TMS and
the fact that there are known individual differences in anatomy, physiology, and likely het-
erogeneity in the neurocircuitry underlying depression, new tools to inform the design of
optimally effective TMS treatment protocols would be helpful. A handful of approaches to
enhance the potency of TMS are reviewed here (e.g., novel coils, image guidance, parameter
optimization), but there is limited knowledge of how to select among these options for an
individual patient or when to abandon the standard treatment protocol of high-frequency
TMS to the left dorsolateral prefrontal cortex (DLPFC) in favor of one of these enhanced
treatment paradigms.
Of particular concern is optimizing outcomes for geriatric patients, who represent the
bulk of those currently receiving ECT. Given the prevalence of cognitive impairment and
dementia in the elderly and given their increased risk of suicide, safe and effective alternatives
for these patients is a compelling public health priority. Unfortunately, some studies (Pallanti
et al., 2012) suggest that the elderly respond less well to TMS than their younger counter-
parts (Aguirre et al, 2011), though not all studies have found this to be the case (Ciobanu,
Girard, Marin, Labrunie, & Malauzat, 2013). While Jorge et al. (2008) found a significant
effect of active TMS relative to sham in vascular depression in the elderly, advanced age and
frontal gray matter atrophy were associated with worse outcomes.
This purported age effect may be multifactorial, relating to cortical atrophy causing
a reduction in the actual delivered dosage of induced electrical current in the brain (If this
were the case, it could be counteracted by delivering a distance-adjusted intensity of TMS as
proposed in by Nahas et al., 2004.), differences in the etiology of depression in the elderly
(e.g., vascular etiology resulting in a disconnection syndrome such that lateral TMS targets
are less well connected with transsynaptic limbic regions that may be vital for antidepressant
response), and/or aging effects on the neuroplastic action of TMS itself, as has been reported
in a preclinical model (Levkovitz & Segal, 2001). There may also be interactions between
age and gender, implicating changes in reproductive hormone status as affecting response to
TMS (Huang, Wei, Chou, & Su, 2008).
Implications for Efficacy of TMS

The modest efficacy of TMS as currently practiced calls for further work directed at enhanc-
ing efficacy, particularly in the medication-resistant and geriatric populations. The field also
needs better and more reliable methods of predicting response and individualizing dosage to
optimize efficacy. In addition to enhancing overall efficacy, approaches to accelerate response
and guidelines for maintenance schedules to prolong remission and prevent relapse are also
needed.
Limitations to the Safety of Clinical TMS

Overall Safety Profile
Overall, TMS has an excellent reported safety profile. Common side effects are typically
mild (including scalp discomfort and headache), and serious side effects (such as seizure)
are rare and have a number of known predisposing factors to help identify patients at great-
est risk. Safety guidelines to inform dosage selection to mitigate risk have been published
(Wassermann, 1998), and consensus guidelines covering level of medical supervision given
specific settings and applications have been developed and widely disseminated (Rossi,
Hallett, Rossini, & Pascual-Leone, 2009). These developments have been important to
inform the safe application of TMS across research and clinical settings.
Seizure Risk
While rare, seizure remains the most significant known risk of TMS. Established safety
guidelines have gone a long way to informing the safe use of TMS in healthy adult popula-
tions and in unmedicated adults who receive treatment with the figure-8 coil as used in the
safety studies. These studies enrolled medically and psychiatrically healthy and unmedicated
adults. However, when these safety studies are extrapolated to real-world clinical populations
and to different coil designs and contexts, there are limits to their ability to inform practice.
Of particular concern is when the guidelines are extrapolated to patients on psychotropic
medications, which are known to affect seizure risk.
Following FDA approval, there have been a handful of reports of seizures induced in
depressed patients receiving TMS with the FDA-approved device at parameters of stimula-
tion that are within the safety guidelines. The FDA Manufacturer and User Facility Device
Experience (MAUDE) adverse-event database contains reports of four seizures in patients
being treated within the safety guidelines with the FDA-approved device. In all cases, patients
were on psychotropic medications with known effects on seizure threshold, and in one case
the patient had a history of generalized seizure disorder. Our knowledge of the safety of
TMS in the absence of concomitant medications is limited by the sample size of the healthy
patients in the safety studies. Therefore, as experience with TMS climbs, a clearer picture of
the true incidence of seizure as a complication of TMS will emerge. It is also the case that
the lack of safety guidelines to inform TMS parameter selection in patients on psychotropic
medications is a significant limitation, as reflected in the postapproval seizures reported to
date. The current evidence supports the conclusion that the seizure risk of TMS in patients
taking psychotropic medications is likely to be higher than in those patients not taking such
medications and that motor threshold determination is not adequate to compensate for that
increased risk.
Other Side Effects

Other side effects reported in the FDA MAUDE database include two cases of retinal detach-
ment (on the side where the TMS coil was placed over prefrontal cortex), two cases of mania,
and one hospitalization for suicidal ideation. While suicidal ideation can be expected in a
severely depressed sample and mania can occur in response to antidepressant medications
and ECT, the report of two cases of retinal detachment (one of which was published; Kung,
Ahuja, Iezzi, & Sampson, 2011) is notable given the possibility that TMS could induce con-
traction of extraocular muscles, causing vibration. A less likely explanation is that currents
may be induced in the retina if the coil is sufficiently close to the eye. As clinical experience
with TMS increases, such unanticipated and low-incidence side effects may begin to emerge,
making field surveillance and voluntary participation in the FDA MAUDE database all the
more important.
Limited Knowledge of Safety in Special Populations

Given the limits to efficacy and safety concerns of the use of psychotropic medications in
children and adolescents and during pregnancy, there is significant interest in the safe use of
TMS in these populations. While the few reported studies of TMS in adolescents described
good tolerability (as reviewed by D'agati, Bloch, Levkovitz, & Reti, 2010), larger samples
will be required to establish rates for low-incidence side effects. As an example, there was a
recently reported case of a seizure in a girl aged 15 years who was treated with TMS and con-
comitant sertraline (Hu et al., 2011). As with adults, children may be more at risk of seizure
with concomitant psychotropic medications during TMS. Given that children (individuals
under 18 years of age) may have a lower seizure threshold than adults, and that there are no
systematic studies of after-discharge threshold with TMS in children/adolescents are were
conducted in adults, a higher level of caution in this age group would seem prudent.
Limits to Extrapolation of Safety Guidelines

from Healthy Samples to Clinical Populations
and Novel Treatment Protocols
It is important to note that safety guidelines were developed for healthy adults who were medi-
cation free, receiving stimulation with a figure-8 coil with mono frequencies, and using motor
thresholds titrated with electromyography EMG—a noninvasive technique for monitoring
muscle activity. Extrapolating to other age groups, concomitant use of seizure threshold alter-
ing medications, other coil types, other stimulation paradigms (e.g., theta burst stimulation
[TBS]), and intensity adjusted to visual twitch rather than electromyographic-determined
motor threshold may affect risk. Indeed, each seizure reported after FDA approval has been
attributed to one or a combination of these factors. The fact that real-world clinical samples
commonly present with medical comorbidities, concomitant medications, and other fea-
tures that post challenges to extrapolation, highlights the need for safety studies that address
patients with these features, which are typically encountered in clinical practice.
Given the modest efficacy of 10-Hz TMS to the DLPFC with the figure-8 coil, signifi-
cant interest has been placed in use of deeper-penetrating coils and more potent parameters of
stimulation such as TBS. According to the 510K approval letter (K122288, Jan. 7, 2013) for
the recently FDA-approved dTMS coil, of 181 patients in the per protocol analysis, one had
a seizure. It is expected that the dTMS coil, which stimulates a larger volume of cortex than
the figure-8 coil, might have a different side-effect profile than that of the figure-8 coil. A few
studies examining TBS in adults and children have described this treatment as generally safe
but have also concluded that larger systematic studies are needed in order to establish safety
(Oberman, Edwards, Eldaief, & Pascual-Leone, 2011; Wu, Shahana, Huddleston, Lewis, &
Gilbert, 2012).
Implications for Safety of TMS

While the side-effect profile has generally been good for TMS, extrapolation to clinical pop-
ulations, concomitant medications, and novel stimulation paradigms may carry a new set of
risks that should be examined.
Limitations to TMS Clinical Trial Design

and Research Methodologies
Sham/Masking
Keys to effective TMS clinical trial design are the validity and plausibility of the sham condi-
tion. A valid sham is key to basic science studies of TMS as well as to studies that evaluate
efficacy across a range of disorders. The purpose of sham TMS is to protect clinical trials from
bias by masking the patient, TMS operator, and clinical raters to treatment condition and to
control for the placebo response by equating the degree of expectancy between the active and
sham treatment arms. The ideal sham would be biologically inactive, match the same expec-
tancy as active TMS, and effectively simulate the ancillary aspects of active TMS (including
the intensive clinician–patient contact, visual look of the coil, manner of holding the coil,
auditory clicking, and somatosenory sensations (scalp sensation, scalp muscle contraction,
discomfort/pain, and potential for muscle twitching in a limb depending on coil placement
and field distribution).
Methods for sham TMS have evolved over time, with significant improvements in
validity (Figure 11.1). However, the search for the perfect sham condition to effectively mask
randomization, control for the placebo effect, and match ancillary sensations and degree of
clinical contact continues.
The original coil tilt sham matched the sound but not the look or feel of active TMS;
with inadequate tilt, it could induce significant stimulation in the brain (Lisanby, Gutman,
Luber, Schroeder, & Sackeim, 2001). The metal shield sham matched the sound and look
of active TMS but lacked the scalp sensation. E-field cancellation at the surface of the scalp
was used in the pivotal trial leading to FDA approval (O’Reardon et al., 2007), but it is
not known whether this was successful in blunting the sensation of active TMS at the scalp.
Other approaches to sham include reversing current flow in the loops of the figure-8 coil
such that they cancel at the intersection and use of the sandwich coil with an active coil on
one side and a sham on the other. However, both of these approaches result in less scalp sen-
sation, which could cue patients (Sommer et al., 2006; Ruohonen, Ollikainen, Nikouline,
Virtanen, & Ilmoniemi, 2000; Hoeft, Wu, Hernandez, Glover, & Shimojo, 2008). Electrical
stimulation of the scalp, which was used in the optimization of TMS for the treatment of
depression trial, was effective in protecting the trial from bias by matching the degree of scalp
sensation between active and sham interventions, in combination with active auditory mask-
ing to match ancillary effects (George et al., 2010).
am TMS
of Sh
Future
u t i o n
Evol Scalp E-
Stimulation
E-Field
Cancellation ?
Metal Shield
Coil Tilt
Make
active
TMS
Simulate feel of quieter
Blunt the feel active and with
of active less scalp
Matching: sensation
Feel +/– X X
Look X X X X
Sound X X X X X
F I GUR E 11 .1 Evolution
of Sham TMS. Over time the approach to sham TMS has evolved, with succes-
sively valid emulation of the sound, look, and feel of active TMS. Future developments may achieve
improvements through engineering advances that yield quieter coils with less vibration and pulse-shape
optimization to reduce scalp sensation.
Future directions for improving sham manipulations may be directed at creating active
TMS systems that are quieter and induce less vibration and scalp sensation than conventional
TMS. This could be achieved through engineering advances and pulse-shape optimization
(Peterchev, Goetz, Westin, Luber, & Lisanby, 2013; Peterchev, Luber, Wagner, Westin,
Lisanby, 2008).
Confound of Neuroplastic Effects of Auditory and

Somatosensory Stimulation
Not only is sham important to control for the placebo effect, it is also important to control
for ancillary auditory and somatosensory stimulation that could conceivably affect outcome
measures independent of their impact on plausibility of the sham condition. For example,
new evidence indicates that tetanic auditory or visual stimulation can induce plasticity in the
brain (for a review, see Clapp, Hamm, Kirk, & Teyler, 2012).
Comprehensive Reporting of Parameters

and Coil Design to Enable Metaanalyses
Addressing the limitations to the efficacy and safety of TMS will rely on emerging evidence
in the scientific literature, which makes accurate reporting vital for useful metaanalyses to
be able to be conducted and inform the field. Given the infinitely large, multidimensional
parameter space, synthesis across studies with divergent methodologies is a challenge. At
minimum, accurate reporting of salient aspects of dosage in the scientific literature may
enable meaningful dose/response relationships to emerge. Guidelines for this reporting
are now available and should further our understanding of what comprises key elements
of the dose of brain stimulation relevant for optimizing efficacy and safety (Peterchev
et al., 2012).
Implications for Clinical Trial Design

Our current knowledge of the efficacy and safety of TMS across clinical applications in
neuropsychiatry hinges on the validity of the sham condition used. However, studies have
used a variety of sham conditions, and only the most recent ones have used a validated sham
that matches the scalp sensation of active TMS. This may explain why early trials had higher
effect sizes than more recent trials. Advances in validated sham manipulations, innova-
tive approaches to reduce the ancillary effects of active TMS so that it is easier to mask,
and increased consistency in the reporting of dosing parameters should enable meaningful
metaanalyses of the published literature and inform the optimization of TMS for clinical
applications.
Placing the Limitations of Clinical

TMS into Historical Context
Evolution of ECT Technique
In reflecting on the limitations and future directions of clinical TMS, it is useful to consider
the historical context of the development of clinical therapeutic interventions in psychia-
try. Here, the gold standard, ECT, is used as an example. ECT has undergone considerable
modification throughout its 75-year history in active clinical use in psychiatry. It has con-
sistently been considered highly efficacious. However, successful evolution of the technique
and refinement of dosimetry has evolved over time, and these changes have ushered in an
improved safety profile.
Significant milestones in the history of ECT include the advent of anesthesia (particu-
larly muscle paralysis, which avoided bone fractures), refinement in patient selection (with
the recognition that it is more effective for mood disorders than the original application of
schizophrenia), and optimization of various aspects of ECT dosing.
Steps in the evolution of ECT dosimetry, which are summarized in Table 11.1, include
approaches to individualize the dosage and to optimize the spatial and temporal compo-
nents of the dose. Our understanding of what is meant by the “dosage” of a neuromodula-
tion treatment has evolved over this time and continues to evolve in response to advancing
understanding of how electrical fields interact with brain function (Peterchev et al., 2012;
Peterchev, Rosa, Deng, Prudic, & Lisanby, 2010). The dosage of an electrical intervention
such as ECT or an electromagnetic intervention such as TMS can be understood in terms of
the spatial distribution of the electric field induced in the brain and in terms of the temporal
aspects of how the field strength varies over time (Figure 11.2). The temporal aspects have the
following two features: the shape and width of each individual pulse and the parameters that
describe the train of pulses (frequency, duration, intertrain interval). We now know that each
of these aspects exerts independent effects on the brain’s response to stimulation. However,
in the ECT field, these parameters are typically combined into a single metric (charge, in mil-
licoulombs), which represents the total area under the curve of the delivered current.
TABLE 11.1 Evolution of ECT Technique
Feature Original State Intermediary Current State Possible Future States

States
Individualization One size fits all Age-based Seizure threshold Individualized pulse
(seizure necessary dosing titration (with fixed amplitude titration
and sufficient) pulse amplitude at 0.8 to compensate for
or 0.9 Amps) anatomical variation
Spatial Shaping One size fits all Electrode placement Experimental electrode
(bilateral electrode options (Right placements (FEAST,
placement) unilateral, Bifrontal) Frontomedial); low
amplitude pulses;
magnetic induction
(magentic seizure
therapy, MST)
Temporal Tuning
Pulse Shape One size fits all Brief pulse Ultrabrief pulse width Novel pulse shapes
(sine wave) width (0.25–0.3 ms)
(1–2 ms)
Train Parameters One size fits all Dosing based on charge Independent
(combines train duration optimization of
with frequency to express freuqency and train
total area under the curve) duraiton
Originally, ECT was a “one-size-fits-all” technique, with limited attention to dosage

beyond what was necessary for the induction of a seizure that was thought to be both nec-
essary and sufficient to ensure efficacy. At the outset, all patients received stimulation with
bilateral electrode placement and sine wave stimulus, and stimulation was applied until a
seizure was induced. Over time it became apparent that individuals differed in their dosage
requirements to induce a seizure, leading to approaches for individualizing the dosage, for
example, age-based dosing and seizure-threshold titration. A series of randomized, controlled
trials provided convincing evidence that dosage exerts a major impact on both efficacy and
side effects (Sackeim et al., 2000, 2008). Thus, the current standard is to individualize ECT
dosage based on empirical titration of each patient’s seizure threshold. An expanded array of
electrode placements is now available in an attempt to target the induced field more precisely
and lessen cognitive side effects.
Interestingly, the spatial components of the dosage (electrode placement) and tempo-
ral components of ECT dosage (pulse shape and train parameters) interact in determining
outcome. For example, ultrabrief pulse width lowers the cognitive side effects of both unilat-
eral and bilateral ECT and lowers the efficacy of bilateral, but not unilateral, ECT (Sackeim
et al., 2008).
Future developments in the field of ECT have focused on identifying new ways to
improve its side-effect profile through optimization of the approach to individualiza-
tion, spatial shaping of the field, and temporal tuning (summarized in Table 11.1). New
approaches to individualization may involve titration of the pulse amplitude. While the
TMS field has long utilized the procedure of motor threshold titration to individualize
pulse amplitude, ECT continues to use a fixed high current. However, individualizing
pulse amplitude can be done with ECT and represents a potential new way of adjusting
Defining Dose
• In Space
– Electrode/coil placement
Electrodes Coil
Right
Bilateral Bifrontal Unilateral
• In Time
– Pulse shape
– Train parameters
Electrodes Coil
Frequency, Duration,
Sine Wave Brief Pulse Ultra-Brief Pulse
Directionality
F I GUR E 11 .2 Defining

Dosage of Transcranial Stimulation. The dosage of ECT or TMS can be character-
ized in terms of how the electric field is distributed in space and how the field strength changes over
time. The spatial distribution is controlled by the shape and placement of the electrodes on the head
(in the case of ECT) and by the shape and placement of the stimulating coil (in the case of TMS). Typical
ECT electrode placements are shown in the insert. The temporal components of the dosage may be
characterized in terms of the shape of each pulse (such as sine wave versus square wave), the width
of the pulse (brief pulse versus ultrabrief pulse), the amplitude of each pulse, and the parameters that
describe the train of pulses (frequency, duration, and directionality).
for anatomical differences that may explain individual heterogeneity in clinical outcomes
(Lee, Lisanby, Laine, & Peterchev, 2012; Lee, Deng, Laine, Lisanby, & Peterchev, (2011;
Lee et al., 2010, 2012).
In terms of spatial optimization, novel electrode placements are under investigation
to better focus the field and spare regions of the brain implicated in cognitive side effects
(Spellman, Peterchev, & Lisanby, 2009; Rosa, Abdo, Rosa, Lisanby, & Peterchev, 2012). The
lowering pulse amplitude also makes the field more focal. The feasibility of low-amplitude
ECT has been reported, and the potential benefits are under active study (Rosa, Abdo,
Lisanby, & Peterchev, 2011). Finally, inducing the seizure magnetically (magnetic sei-
zure therapy [MST]) allows enhanced control over the site and extent of stimulation due
to the lack of impedance from the scalp and skull (Lisanby, Schlaepfer, Fisch, & Sackeim,
2001). Superior cognitive outcomes with MST compared with ECT have been reported
(McClintock et al., 2013; Spellman et al., 2008; Lisanby, Luber, Schlaepfer, & Sackeim,
2003). Preliminary reports of efficacy have been encouraging, demonstrating similar response
rates between ECT and MST (Kayser et al., 2011).
In terms of temporal optimization, moving to ultrabrief pulse shape has already dra-
matically lowered cognitive side effects (Sackeim et al., 2008). The potential value of other
pulse shapes has been proposed on a theoretical basis but has yet to be explored clinically
(Hofmann, Ebert, Tass, & Hauptmann, 2011). Regarding the parameters that describe
the train of pulses, it has been reported that lower frequencies, longer durations, and uni-
directional trains are more efficient (Spellman et al., 2009; Devanand, Lisanby, Nobler, &
Sackeim, 1998).
An unanswered question for the future evolution of ECT includes how best to prevent
relapse following remission. Despite its excellent acute efficacy, relapse post ECT remains
an important clinical challenge (Kellner et al., 2006) and is the focus of ongoing research
(Lisanby et al., 2008).
Implications of Historical Context for Clinical TMS

History has taught us that dosage is key to efficacy and safety and that the approach to dosing
should evolve over time as knowledge of mechanisms emerges. The rational design of neuro-
modulation therapies, including TMS and ECT, will require optimizing the risk/benefit ratio,
which will in turn require discovery of the dose–response relationships that govern how the
brain responds to transcranial stimulation. This work will hinge on careful definition, charac-
terization, and optimization of the dose of TMS, including its spatial and temporal aspects, as
well as approaches to individualizing dose. History has also taught us that relapse prevention
is a critical and as yet unsolved issue, bearing close attention with TMS as well.
We have seen TMS technology evolve considerably since it was first introduced as a
tool in neuroscience in 1985 and as an approved treatment in psychiatry in 2008. While the
field of ECT has had more than seven decades to mature, the TMS field has had only seven
years post FDA approval. Progress has been comparatively rapid, informed by the historical
context of ECT’s history as well as modern engineering approaches to device and coil design,
coupled with computational modeling and neuroscience discoveries.
Future Directions for Clinical TMS

Evolution of TMS Technique
While the field of TMS is young compared with that of ECT, the technology has been rap-
idly evolving, spurred by considerable engineering innovations and neurosciences advances
in understanding of mechanisms. Given the excellent safety profile of TMS, much of the
focus for clinical TMS has been on optimizing efficacy. Current and future approaches to
optimizing clinical TMS, which are summarized in Table 11.2, involve innovations in indi-
vidualization of stimulation, shaping the spatial distribution of the induced field, and tempo-
ral tuning of pulse and train characteristics.
Future Directions in Individualization

of Stimulus Parameters
The current approach to clinical TMS dosing is to individualize pulse amplitude via titration
of the motor threshold (usually visual twitch threshold) and to apply a fixed frequency, train
TABLE 11.2 Evolution of TMS Technique
Feature Original/Current State Intermediary States Possible Future States
Individualization Adjust pulse amplitude Adjust other parameters to

to motor response measured biomarker of target
engagement/plastic response
Spatial Shaping
Coil Placement DLPFC, 5 cm anterior 6 cm anterior to optimal DTI/fMRI informed navigation to
to thumb area motor site; 10-20 EEG transsynaptic targets
system; anatomical MRI
guidance; fMRI guidance
Coil Design Figure 8—superficial dTMS—deep and Novel coil designs to optimize
and focal nonfocal depth/focality trade off; Coils
designed for specific anatomical
targets, informed by realistic
head modeling
Temporal Tuning
Pulse Shape One size fits all Monophasic and Novel pulse shapes—controllable
(dampened cosine biphasic stimulators pulse TMS (cTMS)
waveform)
Train Parameters Mono-frequency trains Complex trains with Selection informed by biomarkers
(10 Hz left, 1 Hz right nested frequencies of target engagement (based on
DLPFC) (theta burst) mechanisms of action or disease
process)
duration, intertrain interval, and number of pulses based on the FDA-approved protocol for
depression. While this approach may be effective for some patients, there are some inherent
limitations that could affect individual response. For example, visual twitch overestimates
motor threshold, and safety guidelines were based on EMG-determined MT (as were the
clinical trials with TMS for depression). We recently reported that visual twitch MT is 11%
higher than EMG-determined MT and that in more than half of patients, use of the visual
twitch MT would have resulted in stimulation beyond the safety guidelines (Westin, Bassi,
Lisanby, & Luber, 2013). This is an especially salient point when considering the additional
confound of concomitant medications, which can further increase risk, making careful MT
determination all the more important for clinical populations.
Regardless of how MT is determined, it is a measure of motor cortex response; how-
ever, it is not a direct measure of response of the brain area targeted in depression (the
DLPFC). While titrating intensity to MT has been established as a means of ensuring safety,
it is not clear that this is the optimal means of ensuring efficacy. This highlights the need for
an “MT-equivalent” for response of cortical areas outside of the motor cortex, such as the
DLPFC. Potentially attractive options worth exploring in this regard include TMS-evoked
potential (TMS-EP) and TMS/ functional magnetic resonance imaging (fMRI) interleav-
ing, though the clinical utility of this approach is yet to be determined.
Furthermore, MT only adjusts amplitude based on response to a single pulse. Clinical
TMS treatment is given in trains of pulses, and MT does not capture individual variability
in response to the cumulative effect of a train of pulses. This highlights the need for a bio-
marker for neuroplastic response to a TMS train. Putative markers of such plasticity include
TMS-EP, which has revealed cumulative effects of TMS pulses in a train (Hamidi, Slagter,
Tononi, & Postle, 2010), and a paired associative stimulation paradigm, which is a marker
of heterosynaptic plasticity and has revealed potentiation following TMS trains as well as
deficient plasticity in certain patient groups (Player et al., 2013).
Beyond individualization of TMS amplitude, leaving the other parameters fixed fails
to take into account all aspects that contribute to dosing. Indeed, emerging literature sug-
gests that other dosing paradigms beyond the current FDA-approved paradigm may be more
effective (e.g., bilateral stimulation, right-sided stimulation, increased number of pulses per
session, MRI-guidance). However, at present, there is little guidance on how to select among
these paradigms for a particular patient or how to individualize the parameters within a par-
ticular paradigm.
Future Directions in Spatial Shaping for Clinical TMS

The spatial distribution of the electrical field that is induced with TMS is driven by coil
placement and coil design. The original coil placement for depression used in most studies
was the DLPFC, identified as the region 5 cm anterior to the optimal site for the primary
motor cortex. While this can be located reliably, there is a high degree of variability in how
well this reaches the DLPFC target, and this variability is expected to result in reduced
clinical outcomes (Herbsman et al., 2009). Basing placement on the 10–20 electroencepha-
lography (EEG) system is considered a more valid method because it adjusts to differences
in head size. Also, this system has improved structural image guidance, which has been
reported to improve antidepressant efficacy (Fitzgerald et al., 2009). However, accounting
for variation in anatomy only tells part of the story. Differences in functional neuroanatomy
should also be considered. fMRI guidance has been particularly useful in improving the
effect size of TMS in cognitive neuroscience studies (Luber et al., 2007, 2008, 2012) and
has been explored in clinical settings as well (Mantovani, Westin, Hirsch, & Lisanby, 2010).
However, more work needs to be done to establish how successful such an approach may
be for depression.
Another intriguing approach for optimizing coil placement in order to reach remote
targets is connectivity-guided coil placement. Fox and colleagues (2012) reported that the
more successful depression targets in the DLPFC demonstrate the greatest anticorrela-
tion with rostral cingulate on resting state fMRI. This is interesting given the emerging
importance of connectivity-informed selection of deep brain stimulation (DBS) target-
ing, using diffusion tensor imaging data (Gutman, Holtzheimer, Behrens, Johansen-Berg,
& Mayberg, 2009). Other future directions for spatial optimization of coil placement
include identification of cortical targets other than the DLPFC that may be relevant for
depression and may have more robust direct connectivity to limbic regions as well as mul-
tifocal targeting.
Regarding coil design, the first FDA-approved coil was a focal figure-8 coil. Recently
FDA approved a deeper penetrating and less focal coil, the H-coil. This coil is reported to
have robust efficacy (Harel et al., 2011; Levkovitz et al., 2009); however, a head-to-head com-
parison with the figure-8 coil has not been conducted. Deeper penetrating coils are attractive
for direct stimulation of deep targets. Nonfocal coils enable the synchronous driving of larger
regions of the cortex, increasing the likelihood of reaching the clinically important targets
but also increasing the likelihood of inadvertently stimulating nontargets, which may impact
its safety profile. As discussed above, changes in coil design can affect seizure risk.
Computational modeling has demonstrated that there is always a depth/focality
trade-off such that the deeper penetrating coils are necessarily less focal (Deng, Lisanby,
& Peterchev, 2013). Nevertheless, these computational tools can enable the design of coils
optimized for specific targets and characterize their degree of focality and spread (Deng,
Peterchev, & Lisanby, 2008).
Future Directions in Temporal

Tuning for Clinical TMS
Much of the focus to date has been on the spatial components of dosing (coil location and
coil design), with less focus on the temporal components. However, the temporal compo-
nents are expected to be key to the induction of plasticity. Temporal components of the
dosage include the pulse shape and the parameters that describe the pulse train.
Regarding pulse-shape optimization, whereas the original TMS devices induced sinu-
soidal waveforms that were not amenable to user control, new engineering developments
have enabled the design of TMS stimulators that can induce a broadening range of pulse
shapes and characteristics (Peterchev, Murphy, & Lisanby, 2010, 2011; Peterchev, Jalinous,
& Lisanby, 2008). We recently demonstrated that the width of the TMS pulse is a powerful
driver of its effect on cortical excitability (Luber et al., 2012). These new technologies pro-
vide researchers with an extended range of pulse shapes and train parameters to chose from
in order to optimize the physiological potency of the stimulation for specific neurobiological
ends (Goetz et al., 2013).
Regarding the parameters that describe the train of pulses, researchers evaluated
whether delivering the total number of pulses in a shorter amount of time could acceler-
ate antidepressant response and had some promising results (Holtzheimer et al., 2010).
Accelerating recovery is particularly important for reducing overall morbidity and reducing
the period of risk for suicide. Others have examined other aspects of the temporal compo-
nents of the train, such as individualizing frequency based on EEG (Price, Lee, Garvey, &
Gibson, 2010) and use of a nested frequency package such as TBS. This technique has been
reported to induce lasting changes in neural oscillations and to induce more potent neu-
roplasticity than monofrequencies of TMS (Noh, Fuggetta, Manganotti, & Fiaschi, 2012).
TBS mimics the natural nesting of frequencies seen in the human brain, with gamma oscilla-
tion power modulated by the phase of theta oscillations.
It has been proposed that neural oscillations and coupling across frequencies in the
power and phase of these oscillations form an integral part of how the brain accomplishes
higher-order cognitive tasks such as working memory and multisensory integration (see,
for example, Lee & Jeong, 2013). As such, there is tremendous potential for physiologically
informed TMS paradigms to expand the clinical utility of TMS. Indeed, it is the temporal
precision of TMS that is a major differentiator of neuromodulation modalities from pharma-
cology. Whereas pharmacology is dependent on half-lives that are typically in the hour to day
to week range, TMS can be given with millisecond precision and in a fashion that is tightly
coupled with the dynamics of endogenous brain function.
Future Directions in Multimodal

Paradigms for Clinical TMS
While studies have long combined TMS with psychopharmacology (typically continuing
previously ineffective antidepressant medications and adding on TMS), the targeted use of
pharmacology to promote TMS-induced plasticity is a novel future direction worth explor-
ing in order to enhance potency and promote durability of effect. Other strategies include
coupling TMS with priming from other devices (such as transcranial direct current stimula-
tion) and with behavioral therapies to promote learning and skill acquisition or to facilitate
extinction learning, as recently reported with the combined use of dTMS along with expo-
sure therapy in posttraumatic stress disorder. Indeed, the feasibility of simultaneous cogni-
tive behavioral therapy and TMS for depression treatment has been reported, but there is yet
to be a controlled trial evaluating this interesting paradigm Vedeniapin, Cheng, & George,
2010). Given the neurorehabilitation literature that suggests that TMS priming of neurore-
habilitation can promote recovery of function (Takeuchi & Izumi, 2012), it stands to reason
that a similar approach could be useful in other neurobehavioral conditions.
Conclusions
When taken in the historical context of ECT, the evolution of TMS technique is advanc-
ing at a comparatively rapid rate. While in the field of ECT it has taken decades to refine
the treatment and discover dose/response relationships, research in the TMS field is rapidly
accumulating and shaping the future of this technology. Whether these advances will trans-
late into clinically meaningful results for patients above and beyond what current technology
has to offer awaits demonstration in the form of randomized controlled trials. The availabil-
ity of sophisticated modeling technologies and engineering advances that were not available
decades ago bodes well for TMS having a more accelerated clinical optimization than was
the case with ECT.
One of the greatest challenges facing clinical TMS is how to optimize the dosage in order
to maximize efficacy and how to individualize the treatment. Indeed, these challenges remain
for ECT as well, particularly with respect to maximizing safety and sustaining remission. The
parameter space of variables that define the dosage of TMS (and ECT) is infinite and mul-
tidimensional. This poses a major challenge to optimizing the risk/benefit ratio of the treat-
ment. Among the components of dosage yet to be optimized with TMS are pulse and train
parameter selection, coil selection and placement, treatment schedule (number of sessions per
day and days per week), factors that may influence response such as concomitant medications,
psychotherapies (during TMS or at a separate time), and other pharmacological, device-based,
or behavioral approaches to prime the state of the brain at the time of stimulation.
Further compounding this challenge, at present we lack sufficient basic knowledge of
how electrical fields interact with the brain to predict dose/response relationships. While
the field of psychopharmacology is informed by the basic disciplines of pharmacokinetics
and pharmacodynamics, the analog disciplines for electrokinetics and electrodynamics are
only now emerging. This calls for a basic discipline at the interface of engineering and psy-
chiatry to inform dosimetry of neuromodulation techniques. Basic research on mechanisms
of action of TMS will be key to optimizing efficacy and safety. New tools are available for
modeling the E field and the neuronal response to stimulation that are likely to be of signifi-
cant help in this regard.
Ultimately the clinical utility of focal brain stimulation, whether with TMS, ECT,
DBS, or other methodologies yet to be validated, depends on our knowledge of the neuro-
circuitry and neurodynamics of neuropsychiatric disorders. The more we know about the
pathophysiology of the disorder in question, the better able we will be to exert clinical ben-
efit through focal neuromodulation.
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Index
Aaronson, Scott, 136 Bienenstock-Cooper-Munro model of plasticity, 38

Ablation studies, 2 Bilateral rTMS, 120
Accelerated rTMS, 27–28 Bipolar disorder, 26, 35, 61, 122–123
Acoustic changes, 34 Blumberger, Daniel M., 98
Adolescent populations, TMS for, 27 Borderline personality disorder, 53
Adverse effects. See also Safety Brain stem regions, viii
acoustic trauma, 34 Brainsway, Inc., 28, 70
autonomic, 36–37 Burt, T., 22
cognitive, 35 Buzsaki, G., 100
loss of consciousness, 107–108
migraine, 34 Calgary Depression Scale for Schizophrenia, 124
monitoring for, 44–45 Capacitor, Leyden jar as, 1
pain, 34 Carcot, Jean-Martin, 2
seizures, 32–33 Carpenter, L. L., 25–26, 58
syncope, 45 Casarotto, S., 108–109
tinnitus, 38 Center for Epidemiologic Studies Depression Scale
Aldini, Giovanni, 1 (CESD), 90
Alzheimer’s disease, 109, 126–127 Centers for Medicare & Medicaid Services, 60, 79
Antidepressant therapies Children and adolescents, TMS for, 34, 37
advantages and disadvantages of, 55–56 Children’s Depression Rating Scale-Revised
as standard treatment, viii (CDRS-R), 27, 91
TMS versus, 22–23, 58 Chronic pain, 125–126
Antidepressant treatment history form (ATHF), 54 Chronic TMS exposure, 40–41
Anxiety, viii, 35 Cingulate gyrus, viii
Aphasia, 127 Clinical efficacy of TMS in depression, 17–31
Assessment of patients, 52–53. See also Patient combination trial, 21
selection electroconvulsive therapy versus, 23–24
Auditory hallucinations, treatment of, 38, 125, 147 future directions for, 27–28
Autonomic adverse effects, 36–37 geriatric depression, 27, 83
Avery, D. H., 23 large-scale RCT results, 18–20
low frequency right sided rTMS, 119–120
Bae, E., 63 metaanalyses of, 21–22
Barker, Anthony, vii, 3, 8, 17, 98 in Parkinson’s disease, 128
Beck Depression Inventory-II (BDI-II), 89 pharmacotherapy versus, 22–23
Beer, Berthold, 3 post stroke depression, 61, 139
Berger, Hans, 103 priming approach, 121
172 | I n d e x
Clinical efficacy of TMS in depression (Cont.) Electrodynamics, 2

response predictors, 24–25 Electroencephalography (EEG)
special populations, 27 brain rhythms measured by, 105–106
TMS rationale for, viii–ix, 145–146 monitoring by, 44–45
treatment-resistant depression, 4, 18 paired-pulse TMS combined with, 106–107
Clinical trial design, limitations in, 157–159 single-pulse TMS combined with, 106
Cochlear implants, 40 sleep affected by TMS with, 107
Cochrane reviews, 125 TMS combined with, 4, 103–105, 108–109
Cognitive behavioral therapy, 28 Electromagnetism, laws of, 8
Coil configuration Electromyography (EMG), 41, 44, 98
"deep" TMS device, 70 Electrophysiology, 17
estimation of TMS intensity and effect, 13–15 Epstein, Charles M., 8
future directions for, 164 Excitatory TMS paradigms, 100–101
H-shaped, 42
overview, 10–12 Faraday, Michael, 2–3, 99
patient selection and, 62 Farzan, F., 100, 106, 108
Combination TMS, efficacy for depression, 37–40 Ferrarelli, F., 107
Connectivity-guided coil placement, 164 Ferreri, F., 107
Connolly, R. K., 23, 26, 57 Ferrier, David, 2
Consent, 72–75 Fibromyalgia, 126
Contraindications and precautions, 45–46 Fiducials (skull landmarks), 11
Cortical pathways, stimulation of, vii Figiel, G. S., 27
Cortical silent period (CSP), 99–100 Fitzgerald, Paul, 107, 117
Cristancho, Mario A., 17 Food and Drug Administration (FDA). See U.S. Food
Current Procedural Terminology (CPT) codes, 79 and Drug Administration (FDA)
Fox, M. D., 12
d’Arsonval, Jacques-Arsène, 3 Frantseva, M., 108
Daskalakis, Zafiris J., 98, 100, 106 Freud, Sigmund, 3
Deep brain stimulation (DBS), 39–40, 143–145 Fritz, Gustav, 2
"Deep" TMS device, 70 Functional magnetic resonance imaging (fMRI), 4
Dementia, 126–127 Functions of the Brain (Ferrier), 2
Deng, Z. D., 10, 12
Depression. See Clinical efficacy of TMS in Galen of Pergamum, 1
depression Galvani, Luigi, 1
Descartes, René, 1 Gamma-aminobutyric acid (GABA) inhibitory
Diagnostic and Statistical Manual of Mental Disorders neurotransmission, 99–100
(DSM-IV-TR), 87 George, Mark S., 1, 3, 17, 22
Diffusion MRI, 33 Geriatric depression scale (GDS), 91–92
Discontinuation rates, 23 Geriatric population, 27, 83
Dorsolateral prefrontal cortex (DLPFC)
depression and abnormal activity in, viii–ix Hadley, D., 28, 42
locating, 11 Hallucinations, 38, 47, 125, 147
pain perception by, 126 Hamilton Rating Scale for Depression (HRSD), 18,
23, 84, 87–88
Education of patients, 72–75 Harvey, William, 1
Effect, estimation of, 13–15 Hearing loss, 34. See also Auditory hallucinations
Efficacy. See Clinical efficacy of TMS in depression Hebbian plasticity, 4
Elderly populations, TMS for, 83 Hitzig, Eduard, 2
Electroconvulsive therapy (ECT) Holtzheimer, Paul E., vii, 21, 27, 136
in depression treatment, viii Hoppenbrouwers, S., 108
efficacy, 54, 57, 136–137
side effects and tolerability, 137–138 ICF paired-pulse paradigm, 101, 107
speed of response, 138 Ilmoniemi, R., 104
technique evolution, 159–162 Implantable pulse generator (IPG), 40
TMS versus, 23–24, 58–60, 119, 138 Infrared neuronavigation, 11
I n d e x | 173
Inhibitory TMS paradigms, 99–100 Beck Depression Inventory-II, 89

Insular cortex, viii Center for Epidemiologic Studies depression scale
Insurance reimbursement, 60, 78–79 (CESD), 90
Intensity, estimation of, 13–15 Children’s Depression Rating Scale-Revised
Interhemispheric signal propagation, 4 (CDRS-R), 91
Internal pulse generator (IPG), 40 Geriatric Depression Scale (GDS), 91–92
International Federation of Clinical Neurophysiology Inventory of Depressive Symptomatology (IDS)
(IFCN), 32 and Quick IDS measurement, 89–90
International Society for ECT and Neurostimulation Montgomery-Asberg Depression Rating Scale
(ISEN), 71 (MADRS), 88–89
Inventory of Depressive Symptomatology (IDS) and neuropsychologic function screening, 92–94
Quick IDS (QIDS) measurement, 89–90 Patient Health Questionnaire (PHQ-9), 90–91
psychometric considerations, 83
Jackson, Hughlings, 2 Medial prefrontal cortex, viii
Janicak, P. G., 22 Medial temporal lobe regions, viii
Jorge, R., 154 Medicare, 78–79
Mesmer, Franz, 1
Kaptsan, A., 61 Metaplasticity concept, 38
Keel, J. C., 72 Midbrain, viii
Kicic, D., 104 Mindfulness therapy, 28
Kimbrell, T., 37 Mini Mental State Examination (MMSE/MMSE-2)
Kozel, F. A., 22 screening, 92–93
Montgomery-Asberg Depression Rating Scale
Landy, Michelle, 17 (MADRS), 18–19, 84, 88–89
Lefaucheur, Jean-Pascal, 32 Montreal Cognitive Assessment (MoCA) measure of
Levels of evidence, 21 cognitive function, 93–94
Leyden jar (as capacitor), 1 Mood-regulation circuit, of brain, ix
Lisanby, Sarah H., 152 Motor cortex stimulation, 101–103, 125–126
Localisation of Cerebral Disease, The (Ferrier), 2 Motor-evoked potential (MEP), 41–42, 98
Long-interval cortical inhibition (LICI), 99–100, Motor-evoked potential (MEP) amplitude,
106–108 100–101
Long-term potentiation (LTP), 4 Motor threshold, 13–14. See also Resting motor
Loo, Colleen, 27, 136 threshold (RMT)
Low frequency right sided rTMS, 119–120 Multimodal paradigms for TMS, 166
Magnetic resonance imaging (MRI), 11, 20, 44 National Institutes of Health (NIH). See U.S.
Magnetic seizure therapy (MST), 138–139 National Institutes of Health (NIH)
Magstim, Inc., 70 Negative symptoms, in schizophrenia, 124
MagVenture, Inc., 70 Neosync, Inc., 70
Maintenance TMS, 153 Neuroimaging, viii, 44
Maixner, Daniel F., 69 Neurological disorders. See Psychiatric and
Major depressive disorder (MDD). See Clinical effi- neurological disorders, TMS for
cacy of TMS in depression Neuronetics, Inc., 70
Mania, 35–36, 61, 122–123 Neurophysiological measure of TMS, 98–116
Mantovani, A., 22 cortical excitability, 101–103
Manufacturer and User Facility Device Experience electroencephalography (EEG)
(MAUDE) database, FDA, 155–156 brain rhythms measured by, 105–106
Massimini, M., 107 paired-pulse TMS combined with, 106–107
Matsumiya, Y., 33 single-pulse TMS combined with, 106
Maxwell, James Clerk, 2–3, 8 sleep affected by TMS measured by, 107
McCall, W. Vaughn, 52 TMS combined with, 103–105, 108–109
McClintock, Shawn M., 82 excitatory TMS paradigms, 100–101
McDonald, William M., vii future directions, 110
McNamara, B., 21 inhibitory TMS paradigms, 99–100
Measurement-based care, 82–97 loss of consciousness studies, 107–108
174 | I n d e x
Neuroplasticity, 4–5, 158 chronic pain, 125–126

Neuropsychiatric disorders. See Psychiatric and neuro- obsessive compulsive disorder, 123
logical disorders panic disorder, 123–124
Neuropsychological screening, 92–94 Parkinson disease, 128
Neurostar rTMS device (Neuronetics), 18–19, 47 post-stroke depression, 61, 128, 139
Neurostimlation intervention development, 136–151 posttraumatic stress disorder treatment, 123
deep brain stimulation, 143–145 schizophrenia and psychosis, 124–125
electroconvulsive therapy (ECT), 136–138 stroke-related neurological impairment, 127–128
magnetic seizure therapy (MST), 138–139 suicidal ideation, viii, 35
repetitive TMS (rTMS), 145–147 Psychometric considerations, in measurement-based
transcranial direct current stimulation (tDCS), care, 83, 87
139–140 Psychotherapy, viii, 59
vagus nerve stimulation (VNS) implantable device,
140–143 Quick Inventory of Depressive Symptomatology
Neurostimulation practitioners, 60 (QIDS) and IDS measurement, 89–90
Noninvasive brain stimulation, 2
Radhu, Natasha, 98
Obsessive-compulsive disorder (OCD), 123, 143 Regulatory aspects, 46–47
Optimization of TMS trial (OPT-TMS), 20 Reimbursement, insurance, 60, 78–79
Orbitofrontal cortex, viii Relapse, in depression, viii
O’Reardon, John P., 17, 25 Repeatable battery for the assessment of neuropsycho-
Outcome predicting and influencing, 60–64 logical status (RBANS), 94
Repetitive TMS (rTMS). See also Psychiatric and
Pain, chronic, 125–126 neurological disorders, TMS for
Pain, from TMS, 34, 38 accelerated, 27–28
Paired-pulse TMS, 106–107 cortical excitability from, vii
Panic disorder, 123–124 developmental stages of, 17
Parietal cortex, viii in neurostimulation intervention development,
Parkinson’s disease, 36, 128 145–147
Patient Health Questionnaire (PHQ-9), 90–91 single-pulse TMS enhanced by, 3
Patient selection, 52–68 standard approaches, 117–119
consultation, 52–54 Research methodology, limitations in, 157–159
evaluation and monitoring, 71–72 Resting motor threshold (RMT), 13–14, 41, 99–101
limitations in methods of, 154 Rosenquist, Peter B., 52
measurement-based care, 83–84 Rosonova, M., 107
outcome prediction, 60–64 Rossi, Simone, 32–33, 42
TMS versus ECT, 59–60
treatment planning, 54–59 Safety, 32–51. See also Seizures
Patterned stimulation, 121 children and adolescents, 34, 37
Pharmacotherapy, TMS versus, 22–23 chronic TMS exposure, 40–41
Policies, TMS, 75–78 cochlear implants, 40
Pollacsek, Adrian, 3 coil, effects of, 12–13
Post-stroke depression, 61, 139 concurrent diseases and, 37–40
Posttraumatic stress disorder (PTSD), 123 contraindications and precautions, 45–46
Potter, Guy, 82 epilepsy, 32–33
Pregnancy, 27, 37 geriatrics, 27, 83
Priming approach, 38, 43, 121 Manufacturer and User Facility Device Experience
Psychiatric and neurological disorders, TMS for, (MAUDE) database, 155–156
117–135 monitoring for, 44–45
Alzheimer’s disease and dementia, 109, 126–127 neuropsychological screening, 92–94
anxiety, viii, 35, 109 patient selection and, 63–64
aphasia, 127 pregnancy, 27, 37
bipolar disorder, 26, 35–36, 61, 122–123 stimulation parameters and, 41–44
borderline personality disorder, 53 tissue toxicity, 33–34
I n d e x | 175
TMS limitations based on, 155–157 TMS limitations, 152–170

Transcranial magnetic stimulation Adult Safety clinical trial design and research, 157–159
Screen (TASS), 63 ECT technique, 159–162
Schizophrenia, 38, 47, 124–125 patient selection methods, 154
Schutter, D., 22, 119 potency, speed of response, and maintenance,
Screening, 72, 92–94 153
Seizures safety, 155–157
management of, 45 TMS theoretical basis, 1–7
risk of, 15, 154, 156 history, 1–3
as TMS acute adverse event, 32–33 modern, 3–4
Self-report inventories, 89 neuroplasticity and, 4–5
Sequenced Treatment Alternatives to Relieve Transcallosal inhibition (TCI), 100
Depression (STAR*D) trial, 23, 58–59 Transcranial direct current stimulation (tDCS),
Sham/masking, in clinical trials, viii, 157–158 139–140
Shelly, Mary, 1 Transcranial magnetic stimulation adult safety screen
Short-interval cortical inhibition (SICI), 100, 107 (TASS), 63
Short latency afferent inhibition, 4 Treatment-resistant depression (TRD), 4, 18
Single-pulse TMS, 106 Turner, E. H., 22
Sleep, TMS and, 63–64, 107
Slotema, C. W., 22, 24 U.S. Food and Drug Administration (FDA)
Speed of response, 153 Manufacturer and User Facility Device Experience
Stroke-related neurological impairment, treatment of, (MAUDE) database, 155–156
127–128 Neuronetics Neurostar rTMS device
Suicidal ideation, viii, 35 approved by, 47
Swammerdam, Jan, 1 rTMS device approved by, vii–viii, 3, 17
"Synchronized" TMS, 70 TMS devices approved by, 70
Syncope, 45 vagus nerve stimulation approved by, 141
U.S. National Institutes of Health (NIH), 14, 18,
Taylor, Joseph J., 1 20, 57
Thalamus, viii
Theta burst stimulation (TBS), 4, 14, 43, 121 Vagus nerve stimulation (VNS)
Tinnitus, 38 developmental difficulties, 143
Tissue toxicity, 33–34 efficacy, 141–142
TMS, administration of, 69–81 implantable devices for, 141
basic equipment, 69–70 insurance coverage for, 60
insurance reimbursement, 78–79 overview, 141
patients side effects and tolerability, 142
education and consent, 72–75 for treatment-resistant patients, 54, 57
selection and monitoring, 71–72 U.S. Food and Drug Administration (FDA)
personnel and training, 71 approval of, 141
standard operating procedures and policies, 75–78 Validity of measurement instruments, 83, 87
TMS devices, 70 Visual hallucinations, 38
TMS, efficacy of. See Clinical efficacy of TMS in Voineskos, A., 109
depression Volta, Alessandro, 1
TMS, future directions for, 162–166
TMS development, 8–16 Wall, C. A., 27
coil configuration, 10–12 Wang, X., 100
core TMS circuit, 8–10
intensity and effect estimation, 13–15 Zanjani, Anosha, 98
safety considerations, 12–13 Ziemann, U., 100

A Clinical Guide To Transcranial Magnetic Stimulation

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Library of Congress Cataloging-in-Publication Data

1 Theoretical Basis for Transcranial Magnetic Stimulation 1

10 Development of Other Neurostimulation Interventions 136

Scott Aaronson, MD Paul Fitzgerald, MD, PhD

Daniel M. Blumberger, MD Mark S. George, MD

Colleen Loo, MD Guy Potter, PhD

Paul E. Holtzheimer and William M. McDonald

Transcranial Magnetic Stimulation

Current Status of TMS for Depression

Rationale for TMS for Depression

Overview of this Handbook

Theoretical Basis for

Overview: From Spirits to Stimulation

Discovery of the Important Concepts Behind

TMS and Neuroplasticity

Core TMS Circuit

Voltage Capacitor Inductor

F I GUR E 2.1 (A)

+ +++ +++ Diode

Voltage Capacitor Inductor

Safety and Other Coil Considerations

Estimating the Intensity and Effects of TMS

TABLE 2.1 Maximum Safe Train Duration as a Function of Intensity

Frequency (Hz) TMS Intensity as % of Motor Threshold

90% 100% 110% 120% 130%

1 >1800 >1800 >1800 > 360 >50

Clinical Efficacy of Transcranial

Results from Large-Scale RCTs

Response Rates (%) Remission Rates (%)

Active - Response Rate Active - Remission Rate

Week 2 Week 4 Week 6 Week 2 Week 4 Week 6

Open-Label Extension Phase of the

NIH’s Optimization of TMS Trial

Open-Label Extension Phase of the NIH Trial

Metaanalyses of TMS Efficacy in Major

TMS versus Pharmacotherapy

Comparative Effect Sizes of TMS, ADM, and ECT - (HAM-D)

TMS Pivotal Study O’Reardon et al., Biol Psy 2007

F I GUR E 3.2 Comparative

TMS versus Electroconvulsive Therapy

Response rates with TMS and ECT

Prior ECT Subgroup (n = 31):

Special Populations: Adolescents, Pregnant,

Adverse Effects Related to TMS

Cognitive and Psychiatric Adverse Events

Autonomic Adverse Effects

Specific Adverse Effects Related to

TMS and Pregnancy

Specific Adverse Effects Related to

Influence of Concomitant Medication

Chronic Exposure to TMS: The Case

Safety Issues for Various Stimulation

Coils for Deep Stimulation

Stimulation Frequency and Duration of Trains and

New Paradigms of Stimulation

Monitoring the Safety of TMS

1 Theoretical Basis for Transcranial Magnetic Stimulation 1

10 Development of Other Neurostimulation Interventions 136