Handbook of Clinical Neurology, Vol.

163 (3rd series)

The Frontal Lobes
M. D’Esposito and J.H. Grafman, Editors
https://doi.org/10.1016/B978-0-12-804281-6.00005-7
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 5

Transcranial magnetic stimulation: Neurophysiological

and clinical applications

MATTHEW J. BURKE1, PETER J. FRIED1, AND ALVARO PASCUAL-LEONE1,2,3*

1
Berenson-Allen Center for Noninvasive Brain Stimulation and Division of Cognitive Neurology, Department of Neurology,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
2
Guttmann Brain Health Institute, Institut Guttmann de Neurorehabilitacio, Universitat Autonoma de Barcelona, Barcelona, Spain
3
Marcus Institute for Aging Research, Hebrew Senior Life, Harvard Medical School, Boston, MA, United States

Abstract
Transcranial magnetic stimulation (TMS) is a safe and noninvasive means of electrically stimulating the brain
by electromagnetic induction. TMS is capable of probing intracortical circuits and modulating cortical activ-
ity in humans; as such it has been instrumental to studying the neurophysiology and functional neuroanatomy
of the frontal lobes. For example, using TMS to induce “virtual lesions”—transient disruption of function in
the targeted brain region—has yielded important insights into the functional organization of the prefrontal
cortex (PFC) with respect to working memory, language, and other core cognitive functions. Whereas neu-
roimaging is typically limited to observing correlations between brain function and behavior, TMS, by inter-
acting with neural circuits, can lead to causal inferences that bridge human, nonhuman primate, and other
model system studies. Applied repetitively in trains of stimuli, TMS is also capable of normalizing aberrant
patterns of cortical activity in the treatment of neurologic and psychiatric disorders. The earliest and most
well-established clinical use of repetitive TMS is in the treatment of medication-resistant depression with
high-frequency stimulation of the left dorsolateral PFC. Research efforts to identify other promising clinical
applications—such as for stroke and Alzheimer’s disease—are rapidly expanding; however, the majority of
these indications have yet to have devices cleared by the FDA for on-label use.

functions as well as its clinical applications for diagnos-

INTRODUCTION
Transcranial magnetic stimulation (TMS) is a noninva-
sive brain stimulation technique that generates brief, rap-
idly changing magnetic fields capable of inducing
electric currents in the brain. It is safe, well tolerated,
and has a very favorable side-effect profile, provided that
safety recommendations are followed. TMS has a broad
range of capabilities that make it an optimal neurophys-
iological tool for studying the function of brain regions
and their associated networks, interrogating brain–
behavior relationships and identifying neurobiologic
substrates of disease. In this chapter, we will focus on
the contribution of TMS to understanding frontal lobe
ing and treating disorders with frontal lobe dysfunction.
We will begin by introducing the context and rationale
for using TMS and provide an overview of its technolog-
ical principles. We will then present a wide range of
research that exemplifies the importance of TMS in the
study of the frontal lobes.
PART I: BASIS AND TECHNOLOGICAL
PRINCIPLES OF TMS
Studying brain/behavior relationships
The ongoing effort to better understand the complex
role of the frontal lobes in cognition has a long and

*Correspondence to: Alvaro Pascual-Leone, M.D. Ph.D., Berenson-Allen Center for Noninvasive Brain Stimulation, Beth
Israel Deaconess Medical Center, KS-158, 330 Brookline Ave, Boston, MA 02215, United States. Tel: +1-617-667-0203,
Fax: +1-617-975-5322, E-mail: apleone@bidmc.harvard.edu
74 M.J. BURKE ET AL.
challenging history. As described in previous chapters,
the functions ascribed to the frontal lobes are extensive
and range from fundamental constructs such as mem-
ory and language to abstract phenomena such as
morality, expectation, and reasoning. In modern times,
the most common approach employed by neuroscien-
tists to study frontal lobe function has been to observe
an individual completing a relevant neuropsychologic
task while recording a given metric of brain function.
Metrics for assessing brain function range from per-
formance on neurophysiological tests to changes in
activity on functional magnetic resonance imaging
(fMRI), positron emission tomography (PET), or elec-
troencephalography (EEG). Though these approaches
have led to many valuable insights, they are limited
by the fact that they are correlational in nature. For
example, one could correlate proficiency at a given
task with the magnitude of a recorded neural state-
change, but this tells you relatively little about the
causal necessity of the studied brain region in such a
relationship.
One approach to establish much-needed causal links
has focused on investigation of patients with specific
focal brain lesions, commonly referred to as lesion
studies. For example, a frontal lobe lesion yielding a
temporally documented pre/postchange in cognitive or
emotional functioning provides causal information that
the damaged brain region may be involved (directly or
indirectly) in symptom generation. This technique has
been used with systematic methods since the early
1900s and was championed by many great neuroscien-
tists such as Alexander Luria (Luria, 1972). Lesion
studies have and continue to provide many important
findings, but they also have several limitations that
may obscure appropriate interpretation of causal rela-
tionships (Pascual-Leone et al., 1999). As eloquently
argued by von Monakow (1853–1930) in his 1910 clas-
sic U€ ber Lokalisation der Hirnfunktion (on localization
of brain function), a lesion is necessary for localization
of function, but it is not sufficient. First, a brain lesion
has an impact on the rest of the brain—an impact
mediated by functional connections that von Monakow
described as diaschisis and that today can be examined
using resting state functional connectivity and network
localization approaches (Boes et al., 2015). Second, fol-
lowing a brain lesion such as a stroke or trauma, the
brain reorganizes itself to compensate for the damaged
structures. This can make it difficult to delineate
changes due to the primary lesion vs effects of neuro-
plastic adaptation. Third, lesions often involve larger
volumes than the specific region being evaluated. This
could include adjacent cortical areas or fiber tracts pass-
ing through a region. Fourth, lesions can often be asso-
ciated with multiple areas of injury or global/diffuse
injury plus focal lesion(s). Finally, and perhaps most
importantly, lesion studies are often limited to case
studies or series and lack experimental control. For
example, one lacks a baseline (prelesion) evaluation
and cannot control for age, comorbidities, or other rel-
evant variables that may also influence brain function in
the context of a new lesion.
TMS overcomes many of the pitfalls described here.
TMS can be used safely and noninvasively to induce
“virtual lesions” in experimentally controlled settings.
Virtual lesions are brief periods of stimulation-induced
neurobehavioral dysfunction caused by transient disrup-
tion of the targeted focal brain region (Pascual-Leone
et al., 2000). This approach allows causal inferences to
be made about the necessity of a given brain region or
network in a cognitive or behavioral process. TMS can
also be combined with other modalities such as EEG
and/or fMRI to provide concurrent real-time, brain-wide
neurophysiological data to support behavioral observa-
tions and establish circuit-level causality. To fully appre-
ciate the concepts underpinning the “virtual lesion”
model and its translational applications, we will briefly
describe the fundamental principles of TMS.
TMS mechanisms
Based on the principles of electromagnetic induction
first described by Michael Faraday in 1831, TMS
utilizes a coil made of wire to produce brief, rapidly
changing current pulses capable of generating strong
(
1–2 T) rapidly fluctuating magnetic fields. The first
demonstration of TMS in a human was performed by
Barker et al. (1985). Since this time there has been a
rapid growth of this field and many technological adap-
tations; however, the core principles remain the same.
The coil is traditionally placed tangentially to the scalp
and induces a magnetic field pulse perpendicular to its
plane that penetrates skin, scalp, and skull, reaching
the brain. In the brain, the magnetic field pulse induces
an electric current perpendicular to the magnetic field
and thus parallel to the plane of the coil. The induced
currents are able to elicit action potentials in neurons
of the targeted brain region (Hallett, 2000). Recent
advances have been made in understanding which neu-
ral elements are activated by TMS. Using epidural cer-
vical electrodes to record the descending volleys along
the corticospinal pathway elicited by single TMS pulses
to primary motor cortex, researchers have mapped out
the “direct” and “indirect” (via mono- and polysynaptic
interneuron circuits) activation of layer-V pyramidal
neurons (Di Lazzaro et al., 2012). However, despite
these advances, the exact mechanisms of TMS-induced
neural activation remain poorly understood and a source
of ongoing debate.
 TRANSCRANIAL MAGNETIC STIMULATION
TMS coils
The coil is the only part of the TMS apparatus that
directly contacts the subject/patient. The rest of the
TMS apparatus primarily consists of energy storage
capacitors, a charging unit, circuits for controlling pulse
parameters, and a user-control interface. Starting with a
simple annulus, there have been different shapes and
sizes of coils available for use. The most commonly used
coil in clinical and research settings is the figure-of-8
coil, which is usually favored due to the relatively high
focality of the induced current (Hallett, 2007). Newer
coil designs, such as the H-coil, have been engineered
to try to allow deeper stimulation beyond the superficial
cortex (Zangen et al., 2005). This is relevant to many
neuropsychiatric fields, as deep TMS techniques have
shown the ability to stimulate deep frontal structures such
as the anterior cingulate (Hayward et al., 2007). How-
ever, it is important to note that this type of stimulation
is not selective for the deep target and there is a depth-
focality trade-off (Deng et al., 2013). A final coil that
should be discussed, to facilitate proper interpretation
of studies described later in this chapter, is the sham coil.
Sham devices attempt to mimic the sensations associated
with active TMS pulses (including an auditory “click”
and somatosensory “tap”), while avoiding delivery of
meaningful stimulation to the brain. A realistic sham
device is critical for maintaining blinding integrity in
comparative neurophysiological and treatment studies
of TMS. The current gold standard sham coil looks, feels,
and sounds indistinguishable from an active coil but is
engineered to shield the brain from the magnetic fields.
Some sham coils also allow for superficial electrical
stimulation of the scalp that simulates TMS tactile sensa-
tions (Davis et al., 2013).
TMS targeting
Once an appropriate coil is selected, a variety of different
approaches can be used to target the brain region of inter-
est. Most relevant to this chapter is the approach for tar-
geting the dorsolateral prefrontal cortex (DLPFC), a
common site of stimulation for neurophysiological, cog-
nitive, and clinical protocols. Most studies start by iden-
tifying the motor cortex “hot spot” of a hand muscle, such
as the first dorsal interosseous. This process involves
applying trials of TMS pulses and observing for muscle
twitches in the target muscle or measuring motor evoked
potentials (MEPs) using standard surface electromyo-
gram (EMG). Once the motor cortex hot spot has been
established, the coil is then moved 5–6 cm anteriorly
along the scalp to approximate the DLPFC location
(Pascual-Leone et al., 1996). Though relatively quick
and practical, subsequent studies have found that this
75
methodology can frequently miss the DLPFC target
due to individual anatomic differences (Pascual-Leone
et al., 1999; Herbsman et al., 2009). Other approaches
attempt to localize DLPFC using measurements related
to conventional 10–20 EEG recording sites (Homan
et al., 1987; Beam et al., 2009). They have found that
more anterior and lateral targets could more closely
approximate DLPFC localization but similar issues
regarding anatomic heterogeneity exist (Pascual-
Leone et al., 1999; Herwig et al., 2003a, b; Herbsman
et al., 2009).
More recently, MRI-based neuronavigation equip-
ment has been utilized to visualize and target the DLPFC
directly (Fitzgerald et al., 2009). This frameless stereo-
taxic method uses standard brain-mapping coordinates
on either a template brain MRI or the subject’s own
MRI that is then coregistered with the TMS coil in 3D
space. This technique is currently the gold standard in
most research settings; however, this process takes time
and requires access to costly, specialized equipment that
may not be feasible in most clinical centers. It is impor-
tant to realize that neuronavigation systems are precise
(i.e., they can assure that all TMS pulses induce a current
of consistent focus); however, accurate targeting depends
on the actual goal of the stimulation and precision does
not necessarily equal accuracy. For example, precise tar-
geting of all stimuli to a given cortical target defined by
structural brain anatomy does not ensure that the same
functional brain region is stimulated across individuals.
Thus it is worth considering the use of functional, rather
than anatomic, defined targets. Recent clinical studies
have shown promising results using resting state fMRI
and functional connectivity to guide TMS targeting in
protocols of rTMS for medication-resistant depression
(Fox et al., 2012a, b). In a validation study of this
technique for left DLPFC targeted TMS in patients with
depression, the strength of the functional connectivity
(negative correlation) between an individual’s TMS
cortical target and the subgenual cingulate predicted
antidepressant response (Weigand et al., 2018). Similar
functional connectivity-based approaches could be
adopted more widely for localizing TMS targets (Fox
et al., 2014).
Obviously, the considerations made here regarding
targeting the DLPFC can be extrapolated and adapted
to targeting other regions within the frontal and prefron-
tal cortex (PFC). For anatomic precision, the use of
neuronavigation and, for target definition, functional
(not just macroanatomic) criteria are desirable. Ideally,
capturing the impact of the applied stimulation and relat-
ing that impact to the measured effects should be
attempted. One way to do this is to use MRI not only
to guide the TMS but also to capture its brain impact.
Real-time integration of TMS and EEG or the use of
76 M.J. BURKE ET AL.
other brain-mapping techniques concurrently with TMS
are also worth considering and will be further
discussed later.
Finally, it should be noted that there are many other
technological considerations, such as pulse shape
(monophasic, biphasic, or polyphasic), coil orientation,
and current direction, that are critical factors to consider
in planning and interpreting the results of TMS experi-
ments but are beyond the scope of this chapter and have
been reviewed elsewhere (Rotenberg et al., 2014).
TMS safety
TMS has been studied in healthy volunteers and patients
around the world for over 25 years. Meta-analyses asses-
sing adverse effects collected in experimental and clini-
cal settings support the overall safety and tolerability of
TMS (Machii et al., 2006; Janicak et al., 2008). Risks
associated with TMS and comprehensive safety protocol
guidelines have been formally outlined by the Safety of
TMS Consensus Group of the International Federation of
Clinical Neurophysiology (Rossi et al., 2009; Rossini
et al., 2015). Briefly, the most commonly reported
side-effect of TMS is headache or neck pain, which is
believed to be related to muscle tension due to repetitive
muscle twitches and scalp tapping sensation, as well as
from tightly fitted caps/headbands or positioning of the
participant. This pain is generally short-lived and either
resolves spontaneously or with over-the-counter analge-
sics. The main rare, but serious, potential adverse effect
of TMS is the induction of a seizure. There have been less
than 20 reported cases of TMS-induced seizures since
initial safety guidelines were published in 1998
(Wassermann, 1998) and the commonly quoted risk is
less than 1 in 1000. This risk applies almost exclusively
to repetitive pulse TMS (rTMS), rather than single-pulse
TMS. In predisposed individuals, for example patients
with epilepsy, the risk is higher, but still relatively low,
around 1%–2% (Bae et al., 2007). TMS-induced seizures
are considered provoked events and there has been no
associated risk of generation of epilepsy. Other rare
events include potential hearing loss related to the
TMS clicking sounds (mitigated by wearing earplugs),
syncope (related to anxiety or anticipation of TMS),
and occasional reports of transient cognitive, mood, or
neuropsychiatric symptoms. The general conclusions
are that the risk of serious adverse effects is very low
as long as safety guidelines and recommendations are
adhered to.
TMS protocols
TMS can generally be applied in single pulses, pairs of
pulses, or trains of repetitive pulses. Single-pulse TMS
of the motor cortex is nearly ubiquitous in all TMS stud-
ies as a way to identify the subject/patient’s resting motor
threshold (RMT). The RMT is a measure of cortical
excitability typically defined as the minimal intensity
needed to induce a visible muscle contraction or MEP
larger than 50 mV at least 50% of the time (Rossini
et al., 2015). The motor threshold is frequently used as
a reference to set the intensity of stimulation (e.g., inten-
sity of 80%–120% of RMT) for subsequent protocols,
and safety recommendations are often based on extrapo-
lations of applied TMS intensity in relation to the RMT
(Rossi et al., 2009). It is, however, not always necessary
to set the intensity of TMS based on the RMT. Safe pro-
tocols can be developed inferring stimulation intensity
from other measures, for example the intensity to evoke
a phosphene when targeting the occipital cortex (phos-
phene threshold) or the intensity to evoke a TMS-
induced electroencephalographic potential (transcranial
evoked potential, TEP) or simply setting a given stimu-
lator output intensity (Machii et al., 2006).
A single TMS pulse can also be delivered to the motor
cortex to measure the cortical silent period (cSP). This
silent period is a transient suppression of EMG activity
following a TMS pulse during voluntary muscle contrac-
tion and is believed to measure GABA B receptor-
mediated cortical inhibition (Ziemann et al., 2015).
Beyond these two commonly used measures, single-
pulse TMS has also been used extensively within and
outside the motor cortex in TMS neurophysiological
studies. Single TMS pulses can be timed to disrupt the
ongoing function of a target brain region, which will
be discussed further in the section focusing on virtual
lesions.
Paired-pulse TMS paradigms are primarily used to
record measures of intracortical excitability within, or
connectivity between, brain regions. Two TMS pulses,
a conditioning stimulus and a test stimulus, are delivered
in close succession with varying interstimulus intervals
and intensities. The modulation of the test stimulus by
the conditioning stimulus is typically the primary mea-
surement of interest. Paired-pulse measures include short
interval cortical inhibition (SICI), long interval cortical
inhibition (LICI), intracortical facilitation (ICF), interhe-
mispheric inhibition (IHI), and short-latency afferent
inhibition (SAI) (Kobayashi and Pascual-Leone, 2003;
Valero-Cabre et al., 2017). Please see Table 5.1 for tech-
nical descriptions of these measures. Except for the latter
two, the test and conditioning stimuli are applied to the
same cortical region (typically in the motor cortex).
For IHI, interhemispheric connections are typically eval-
uated by delivering a conditioning stimulus to the ipsilat-
eral M1 and a test stimulus applied to the contralateral
M1 (Ferbert et al., 1992). However, targeting nonmotor
areas and recording TEPs as a measure of IHI is also
 TRANSCRANIAL MAGNETIC STIMULATION
Table 5.1
Paired-pulse paradigms—illustrated by applications to motor cortex.
Measure Stimulation parameters
SICI Intensity of CS ¼ subthreshold (e.g., 80% of RMT)
ISI ¼ 1–5 ms
LICI Intensity of CS ¼ suprathreshold (e.g., 120% of RMT)
ISI ¼ 50–200 ms
ICF Intensity of CS ¼ subthreshold (e.g., 80% of RMT)
ISI ¼ 10–17 ms
IHI Intensity of CS ¼ subthreshold (e.g., 80% of RMT)
ISI ¼ 8–10 ms
SAI CS ¼ applied to peripheral nerve (Median nerve)
ISI ¼ 20 ms
When applied to the motor cortex, response is measured by changes in motor evoked potential amplitude (decrease for inhibition and increase for
excitation). Note, however, that these paradigms can be adapted for study of nonmotor cortical regions and TMS electroencephalographic evoked
potentials can be recorded as responses. Test stimuli used in paired-pulse studies is typically delivered at 100%–120% of resting motor threshold.
CS, conditioning stimulus; ISI, interstimulus interval; RMT, resting motor threshold; SICI, short interval cortical inhibition; LICI, long interval
cortical inhibition; ICF, intracortical facilitation; IHI, interhemispheric inhibition; SAI, short-latency afferent inhibition.
possible. For SAI, the conditioning stimulus is an electri-
cal current applied to a peripheral nerve (typically the
median nerve) and the test stimulus is applied to the con-
tralateral motor cortex (Tokimura et al., 2000). The
paired-pulse technique has been used to investigate the
effects of CNS-active drugs (Ziemann et al., 1996) and
to study the pathophysiology of various neurologic and
psychiatric diseases (Maeda and Pascual-Leone, 2003;
Chen et al., 2008). The primary goal for the latter
research has been to develop diagnostic biomarkers of
disease, which will be discussed in the last section of this
chapter.
Repetitive pulse TMS is an umbrella term that refers
to any combination of three or more pulses of a set inten-
sity delivered at a frequency of at least 0.5 pulses/s;
rTMS may be delivered across a wide range of frequen-
cies, train patterns, and durations. Unlike the transient
effects of single- and paired-pulse TMS, longer trains
of rTMS have been shown to produce changes in activity
and metabolism that outlast the stimulation itself.
Accordingly, its effects can be divided into two main
categories: “online” effects (those that occur during stim-
ulation and are typically disruptive in nature) and
“offline” effects (those that outlast the stimulation and
are typically neuromodulatory in nature). First, rTMS
trains can cause short-term “online” interference effects
that can disrupt the function of a targeted brain area. This
concept and its relevant applications will be discussed
further in the section on virtual lesions. Second,
“offline” effects can be sustained long after the end of
the stimulation protocol and are believed to be mediated
by neuroplastic mechanisms related to synaptic
77
Response Proposed mechanism
Inhibitory GABA-A receptor
Inhibitory GABA B receptor
Excitatory Glutamate
Inhibitory Transcollosal inhibition
Inhibitory Sensory-mediated inhibition of motor
cortex (Cholinergic activity)
modulation via long-term depression and long-term
potentiation. Mimicking these respective processes,
low-frequency trains (e.g.,
1 Hz) tend to result in sup-
pression of activity/excitability and high-frequency stim-
ulation (e.g., 10–20 Hz) tend to result in excitatory effects.
Theta-burst stimulation is a more recent rTMS proto-
col that delivers bursts of three 50-Hz pulses repeated at
5 Hz, which is within the theta band of human neural
oscillatory activity (Huang et al., 2005). The parameters
for this methodology are based on coupling of theta and
gamma wave patterns found to be powerful inducers of
neuroplasticity in animal models (Larson and Lynch,
1986). Similar to low-frequency rTMS, continuous
theta-burst stimulation typically leads to cortical inhibi-
tion and, similar to high-frequency rTMS, intermittent
theta-burst stimulation typically leads to cortical excita-
tion. Theta burst has been shown to induce neuroplastic
changes very quickly and efficiently, which makes these
protocols ideal indices of cortical plasticity (e.g., dura-
tion of posttheta-burst response) (Suppa et al., 2016).
Please see Fig. 5.1 for an overview of the primary
TMS protocols.
The neuromodulatory ability of rTMS, both theta-burst
and traditional protocols, has led to novel treatment strat-
egies for a variety of neurologic and psychiatric disorders,
which will be discussed later in this chapter. Though
an extensive body of basic science and human studies sup-
ports the general mechanisms of rTMS proposed previ-
ously (Hallett, 2007), it is important to stress that the
binary “excitatory”/“inhibitory” classification, commonly
used in the TMS literature, likely represents an over-
simplification of complex, variable, and incompletely
78 M.J. BURKE ET AL.

Fig. 5.1. Overview of common TMS stimulation protocols. (A) Paired-pulse paradigm: dotted line, conditioning stimulus; black
line, test stimulus; time between stimuli, interstimulus interval and (B) gray underline in theta-burst protocol represents a burst of
three pulses at 50 Hz with an interval of 250 ms between bursts. A common protocol for intermittent theta burst would be 2 s of
bursts followed by 8 s off, repeated sequentially. As described in more detail in the text, binary labels of “excitatory” or “inhibitory”
are used for practical purposes, but interindividual and intraindividual variability exists.

understood effects. For example, rTMS can have very high
interindividual variability and the same frequency that
results in excitatory effects in one individual could have
inhibitory effects in another (Maeda et al., 2000a, b;
Hamada and Rothwell, 2016; Jannati et al., 2017). Further-
more, TMS also has “state-dependent” effects within the
same individual (Silvanto and Pascual-Leone, 2008). Sim-
ply put, the ongoing or basal brain state at the time of stim-
ulation strongly impacts the observed TMS effect. When
unaccounted for, this can lead to considerable heterogeneity
and difficult-to-interpret results. However, when appropri-
ately controlled, state-dependency can be manipulated to
purposively shape the direction and/or magnitude of
TMS effects. This topic has been explored at multiple
levels, from behavioral (e.g., level of arousal) to neurophys-
iological (e.g., type of EEG waveform present) and has
been comprehensively reviewed elsewhere (Silvanto and
Pascual-Leone, 2008).
Another important stipulation is that the vast majority
of studies assessing the effects of TMS are based on stud-
ies stimulating and recording output from the motor cor-
tex. However, many TMS studies target regions outside
of the motor cortex, such as the DLPFC. Whether or
not the same or similar excitatory/inhibitory changes
occur in such nonmotor brain regions remains largely
unanswered. If studies do not acknowledge the implicit
assumptions about such protocols, this can lead to spec-
ulative interpretation and misleading claims about the
structure–function relationships being investigated.
Techniques that combine TMS with concurrent measure-
ment of neurophysiological data outside of the motor
cortex, such as TMS-EEG and TMS-fMRI, are critical
tools to begin understanding these questions.
TMS-EEG and TMS-fMRI
TMS-EEG allows one to “perturb” the brain with pulses
of TMS and then use EEG to measure its effects. TMS
pulses produce a series of EEG waveforms that are
referred to as TEPs (Ilmoniemi et al., 1999). These TEPs
are commonly defined according to time-point and the
direction of inflection (e.g., N15, P30) and last up to
300 ms after the TMS pulse (Komssi and K€ahk€onen,
2006). TMS-EEG has the ability to map motor and
nonmotor changes in cortical excitability, evaluate con-
nectivity between brain regions, and measure frequency
bands of intrinsic oscillations generated after perturbation
(Shafi et al., 2012, 2014; Chung et al., 2015). The combi-
nation of this rich output data with millisecond temporal
resolution makes TMS-EEG an extremely powerful tool
 TRANSCRANIAL MAGNETIC STIMULATION
to probe the neurophysiological effects of TMS. How-
ever, it should be noted that this tool is still in develop-
ment. Ongoing efforts by research groups around the
world are trying to optimize approaches to clean artifacts
produced by the TMS pulse and associated peripheral
sensations (van de Laar et al., 2016) and to ensure that
the data collected is robust and has good test–retest reli-
ability (Kerwin et al., 2017).
TMS has also been successfully paired with neuro-
imaging modalities such as fMRI and PET. TMS-fMRI
provides a platform for conducting similar “perturb
and measure” studies and provides additional value
toward better understanding brain-wide TMS effects
(Fox et al., 2012a, b). TMS-fMRI offers superior spa-
tial resolution (but reduced temporal resolution) to
TMS-EEG, which is particularly advantageous for
identifying activity in remote brain regions and connec-
tivity patterns during TMS stimulation (Ruff et al.,
2009). While this technique has been shown to be tech-
nically feasible, high-quality systematic methods to
remove artifacts and improve signal-to-noise ratios
remains an ongoing process (de Lara et al., 2017).
Finally, from a logistical perspective, the specialized
equipment required for TMS-fMRI studies could pose
a barrier to its more widespread use as a clinical
research tool.
79
PART II: TMS AS A PROBE FOR FRONTAL
LOBE PHYSIOLOGY
Virtual lesions, chronometry, and
neuromodulation
TMS applied as single pulses or trains of repetitive pulses
can be used to transiently disrupt a targeted brain region,
creating a “virtual lesion” (Pascual-Leone et al., 1999;
Valero-Cabre et al., 2017). The mechanisms underpin-
ning this technique are complex but will be summarized
briefly. The experimental setup typically involves perfor-
mance of a cognitive/behavioral task while the subject is
simultaneously being stimulated by TMS. The TMS
pulses are localized to a brain region believed to be impli-
cated in the function of interest (e.g., based on previous
neuroimaging or lesion studies). These pulses effectively
act as electrical interference by depolarizing and keeping
targeted neurons refractory such that they are unable to
contribute to the coding of a given process. Changes in
task performance can be assessed by comparing active
TMS stimulation trials to either trials of no stimulation
or, ideally, a sham TMS trial. The latter helps control
for factors involved in TMS delivery that are not specific
to the targeted stimulation (e.g., sound clicks, tactile
scalp sensations, and placebo/expectation-based effects).
See Fig. 5.2 for a schematic depiction of the virtual lesion

Fig. 5.2. General framework for TMS “virtual lesion” neurophysiological studies. In this example, TMS is delivered in single
pulses or repetitive trains to a target brain region concurrently with the selected cognitive task. TMS-induced disruption in task
performance is evaluated by comparison to either completing the task with no stimulation or, ideally, a sham coil control group.
EEG and fMRI can be added to the experimental setup to provide valuable additional neurophysiological data.
80 M.J. BURKE ET AL.
methodology. Additional chronometric methodological the precise definition of executive functioning is evolv-
components can be added to this design to determine ing, its core components are commonly acknowledged to
the time at which the function of a given brain region include inhibition and interference control (i.e., the abil-
becomes causally critical (Walsh and Pascual-Leone, ity to suppress certain behaviors in favor of others),
2003). This protocol harnesses the high temporal resolu- working memory (the ability to maintain and manipulate
tion of single pulses or brief TMS trains that can be information in the absence of persistent perceptual
sequentially delivered during specific time windows in input), and cognitive flexibility (the abilities to think cre-
relation to the behavioral task. The statistical analyses atively, respond quickly to changing circumstances, and
employed by these studies can be complicated but essen- choose between multiple strategies). Along with atten-
tially compare times that TMS stimulation impacted per- tion, executive functions underlie nearly all other higher
formance with times when it did not. Chronometric TMS cognitive abilities (Courtney, 2004).
studies have been invaluable in understanding the tempo- The earliest and most convincing evidence for the
ral sequence of complex cognitive/behavioral functions. role of the PFC in executive functions came from obser-
In some TMS neurophysiological studies, longer vations of patients with traumatic brain injuries or
trains of rTMS are applied prior to the task as a way of other naturally occurring lesions (including stroke and
modulating activity in the target brain region instead of tumors). Patients with damage to the PFC often exhibit
stimulating during the task to induce online disruption. changes in personality, mood, social behaviors, and cog-
Depending on the desired neuromodulatory effect, pre- nitive functions that are collectively referred to as dys-
task rTMS can be applied with different parameters executive syndrome (Thompson-Schill et al., 2002; du
aimed to induce an excitatory or inhibitory effect. This Boisgueheneuc et al., 2006; Kumar et al., 2013). Indeed,
technique is based on short-term plasticity mechanisms the original term for the constellation of symptoms was
rather than electrical interference and can also be used frontal lobe syndrome, acknowledging the common
to shed light on brain–behavior relationships. location of damage in the PFC. However, there are many
Finally, it is important to emphasize that TMS neuro- challenges inherent in using naturally occurring lesions
physiological methods do not solely implicate causality to infer structure–function relationships about the brain.
of the brain structure directly stimulated but also the neu- Studies in nonhuman animals (mainly rhesus macaque
ral network that the region/node may be connected to. and other primates) and neuroimaging studies in humans
The previously described TMS-EEG and TMS-fMRI have provided critical supporting evidence, but each
perturbation paradigms have provided the best evidence of these approaches in turn suffers from its own limita-
to support this critical principle. Many cognitive func- tions. While precise lesions and baseline testing can be
tions ascribed to the frontal lobes have been studied using performed in nonhuman animals, their cognitive abili-
TMS neurophysiological techniques. However, as per ties and brain structures are inarguably different from
the previous qualifier, it is perhaps best to conceptualize humans, which limits the generalizability of any infer-
such “frontal lobe functions” as network functions with ences that can be made. In the case of functional neuro-
critical nodes residing in frontal lobe structures. In this imaging in humans, fMRI and EEG can demonstrate the
section, we will focus on the core PFC topics of working spatial distribution of hemodynamic responses and the
memory and executive functions. We will also briefly temporal dynamics of summed postsynaptic activity,
discuss language processing and provide a few other respectively, that are associated with a given cognitive
more abstract examples that encapsulate the wide spec- process. However, the inferences that can be made are
trum of TMS’s utility in studying the frontal lobes. largely correlational in nature and influenced by choices
in data processing and analysis routines.
With the advent of noninvasive brain stimulation, it
Memory and executive functions
has been possible to directly interfere with the ongoing
With its location rostral to the primary motor and premo- activity of a specific brain area in a temporary, reversible
tor cortices, the PFC is chiefly responsible for integrating manner in awake, healthy humans. While the “virtual
information from the rest of the brain for the purpose of lesions” induced by rTMS do not replicate the complete
planning and executing complex goal-directed behavior. loss of function of an invasive lesion or reversible
In this role, the PFC is often conceptualized as the central deactivation, they nonetheless have the capacity to
executive of the brain (i.e., the pinnacle of top-down pro- change neural activity in a manner sufficient to draw
cesses) and its range of cognitive abilities are described causal inferences regarding brain–behavior relation-
as executive functions (also executive control or cogni- ships. Moreover, the possibility of inducing bidirectional
tive control) (Diamond, 2013). These functions encapsu- changes in activity and metabolism (i.e., decreasing or
late purposeful mental activity contrasted with automatic increasing activity depending on the frequency and pat-
or routine behaviors (i.e., running on “autopilot”). While tern of stimulation) provides for the relatively unique
 TRANSCRANIAL MAGNETIC STIMULATION
observation of enhanced cognitive performance rather
than only looking at diminished or lost functions.
Indeed, some of the earliest reports of the impact of pre-
frontal rTMS on cognition came from improvements in
working memory and attention following treatment of
medication-resistant major depression (Guse et al.,
2010; Martin et al., 2017).
TMS and working memory
Numerous studies have used rTMS, either in short trains
to disrupt ongoing activity or longer regimens to mod-
ulate activity, to demonstrate the causal role of the PFC
to WM (Pascual-Leone and Hallett, 1994; Mottaghy
et al., 2000, 2002a, 2003a), including distinguishing
contributions of PFC from posterior parietal cortex
(PPC) (Koch et al., 2005; Postle et al., 2006; Hamidi
et al., 2008, 2009), and/or functionally dissociate
WM by process and/or type of information (Mottaghy
et al., 2002b; Sandrini et al., 2008; Zanto et al., 2011;
Fried et al., 2014). As discussed in the following para-
graphs, the evidence gained from these studies is some-
what inconsistent, reflecting in part the wide range of
approaches (i.e., rTMS protocols, study populations,
and the cognitive assessments employed) but also likely
the natural individual variation in the organization of
the PFC.
In one of the earliest studies to investigate the segre-
gation of short-term/working memory by process,
Pascual-Leone and Hallett (1994) were able to disrupt
recall by applying short trains of high-frequency rTMS
to either left or right lateral PFC, but not M1, during
the delay period of a delayed response task. Extending
these findings, Koch et al. (2005) used a spatial sequence
matching task to compare right PFC and PPC and
observed PFC TMS impacted performance during both
the delay and decision periods, while PPC stimulation
impacted only the delay. In a series of studies using a
spatial delayed match-to-sample task, Hamidi et al.
(2008, 2009) found TMS (to either hemisphere) affected
the delay period when applied to PPC, but not PFC,
while the decision period was selectively impacted by
stimulation of the PFC, but not PPC. Several other stud-
ies similarly failed to find effects on WM of PFC stim-
ulation during the delay period (Herwig et al., 2003a, b;
Postle et al., 2006; Luber et al., 2007), implying the PFC
is more associated with the executive aspects of WM
(i.e., monitoring, manipulating, inhibiting) rather than
simple maintenance or short-term storage over a delay.
This is consistent with single unit recording studies
(Fuster and Alexander, 1971; Chafee and Goldman-
Rakic, 1998) and lesions/deactivation studies (Bauer
and Fuster, 1976; Funahashi et al., 1993; Moore et al.,
2012) in nonhuman primates.
81
Researchers have also used rTMS to understand how
the PFC is segregated with respect to domain, or the
type of information in WM. Mottaghy et al. (2002b)
applied 1-Hz rTMS to temporarily suppress local activity
in one of three regions of left PFC: dorsomedial PFC
(DMPFC), dorsolateral PFC (DLPFC), and ventrolateral
PFC (VLPFC). The impact was measured as a pre-/
postchange in performance on a delayed response task
using either faces or dots in different locations. The
authors found that accuracy on the spatial dot WM task
was reduced following stimulation of either DMPFC or
DLPFC, while the face WM task was impacted by stim-
ulation of either DLPFC or VLPFC (Mottaghy et al.,
2002b). These findings suggest a dorsal–ventral axis
within the lateral PFC for spatial vs nonspatial informa-
tion. This is consistent with a model of information pro-
cessing in nonhuman primates, in which the dorsal and
ventral segregation of visual information (Ungerleider
and Mishkin, 1982) is maintained within the lateral
PFC (Petrides and Pandya, 1984; Barbas, 1988).
An alternative model suggests that human networks
for WM are similar to language in displaying a left/right
hemispheric segregation depending on whether or not the
information in storage can be verbalized (Acheson et al.,
2010). Consistent with this model, Fried et al. (2014)
used 1-Hz rTMS to separately modulate activity in the
left and right DLPFC and assessed performance using
verbal and spatial versions of a 3-back task. The authors
found evidence of a subtle double dissociation: putatively
reducing left DLPFC activity tended to both decrease ver-
bal performance while increasing spatial accuracy, while
the opposite was observed when the right DLPFC was
stimulated (Fried et al., 2014). Some TMS studies have
found similar evidence of a verbal/spatial hemispheric
specialization (Mull and Seyal, 2001; Sandrini et al.,
2008), while others have failed to find such a distinction
(Oliveri et al., 2001; Mottaghy et al., 2002a, 2003a; Rami
et al., 2003; Postle et al., 2006).
To reconcile these inconsistencies, it has been sug-
gested that the PFC is organized by both domain and
the type of process (Sandrini et al., 2008; Zanto et al.,
2011). Accordingly, the left and right PFC process both
verbal and nonverbal information but are selectively
engaged depending on the task demands. Sandrini
et al. (2008) tested this theory by comparing a combined
verbal/spatial n-back task (letters appearing in different
spatial location and subjects had to attend to one aspect
while inhibiting the other) with traditional single-domain
versions. Using a short train of 10-Hz rTMS, the authors
reported a lateralized interference only for the combined
stimuli version, suggesting the left and right DLPFC
were responsible for inhibiting verbal and spatial aspects
of the stimuli, respectively (Sandrini et al., 2008). While
the organization of the PFC with respect to WM remains
82 M.J. BURKE ET AL.
a topic of debate, the “virtual lesion” approach offered by
TMS has and will continue to play an important role.
A detailed table of TMS neurophysiological studies of
memory has been previously completed and is available
elsewhere (Brem et al., 2013).
TMS and other executive functions
TMS has also been used to investigate the role of the
PFC in attention and other executive functions such as
inhibitory/cognitive control and cognitive flexibility
(e.g., set-shifting, verbal fluency) (Guse et al., 2010;
Lowe et al., 2018). In a series of experiments,
Vanderhasselt et al. (2006a, b, 2007) investigated the role
of the DLPFC in inhibitory control, set-shifting, and top-
down attentional processes. The authors observed that
10-Hz rTMS to the left DLPFC improved reaction times
on the Stroop task for both congruent and incongruent tri-
als (Vanderhasselt et al., 2006a, 2007), while targeting
the right DLPFC improved reaction times for cued trials
on a task-switching paradigm (Vanderhasselt et al.,
2006b). By comparison, Huang et al. (2004) found no
change in go–no go task performance following 5-Hz
rTMS to the left DLPFC. Smirni et al. (2017) used
1-Hz rTMS to both the right and left DLPFC and reported
decreased verbal fluency after 1 Hz to the left but
increased after 1 Hz to the right. While these experiments
were conducted in healthy individuals, many other
studies have used rTMS to try to improve memory and
executive functions in clinical populations. These appli-
cations will be discussed further in the section “Part III:
Clinical Applications”.
Validating behavioral results with
neuroimaging and EEG
When interpreting reports of behavioral changes induced
by neuromodulatory regimens such as rTMS, it is critically
important to be aware of the assumptions made regarding
the physiological mechanisms behind the observed
changes. As discussed in the section “Part I: Basis and
Technological Principles of TMS”, the most direct evi-
dence for the modulatory effects of rTMS in humans come
from measuring its effect on the amplitude of MEPs eli-
cited by single-pulse TMS to the hand region of primary
motor cortex (Pascual-Leone et al., 1994; Maeda et al.,
2000a, b). It is therefore enticing to assume that because
low- and high-frequency rTMS protocols in the motor
cortex tend to decrease and increase average MEP ampli-
tudes, respectively, that the same protocols would produce
a similar effect in nonmotor regions such as the PFC.
Consistent with this assumption, Valero-Cabre et al.
(2007) used radiolabeled glucose injections in the
cat to demonstrate that metabolism (glucose uptake)
increased following 20 Hz and decreased following
1 Hz over the supersylvian region (homologous to pri-
mate intraparietal sulcus). In humans, attempts have
been made to better understand the impact of rTMS
in the PFC by combining it with neuroimaging methods
such as fMRI (Herwig et al., 2003a, b), PET (Mottaghy
et al., 2000, 2003b), and EEG (Zanto et al., 2011;
Shields et al., 2018). Herwig et al. (2003a, b) were
among the first to use task-based activation from fMRI
to guide TMS, an approach that is now widely used
(Acheson et al., 2010; Zanto et al., 2011). Other studies
have used fMRI to map the physiological changes
induced by rTMS: Andoh and Paus (2011) demon-
strated high-frequency rTMS reduced task-associated
activity on the homologous region of the contralateral
hemisphere; Esslinger et al. (2012) observed 5-Hz
rTMS of the right DLPFC induced improvements in
reaction time on an n-back task that were accompanied
by hemodynamic changes in a distributed network of
regions functionally connected to the DLPFC (though
local changes were not observed).
In a series of experiments using PET, Mottaghy et al.
(2000, 2003b) demonstrated that rTMS-induced modula-
tion of WM performance resulted from decreasing
regional cerebral blood flow levels locally within the
DLPFC but also by disrupting the balance of activity
across a frontoparietal WM network. Zanto et al. (2011)
used fMRI to guide the selection of rTMS targets in the
PFC and used EEG to understand its top-down effects
on parietal and occipital cortices. They found that reduc-
tions in task accuracy were accompanied by attenuation of
the P1 component associated with attentional modulation
of sensory features. Similarly, Shields et al. (2018) used
changes in task-evoked EEG activity to help explain
how 1-Hz rTMS to the DLPFC blunted practice effects
for young, but not old, participants. Li et al. (2017) used
EEG to provide mechanistic insight into the impact of
multiple daily 10-Hz rTMS sessions targeting the left
DLPFC on cognitive control. They found an improvement
in reaction time on the Stroop task that was associated with
increased amplitudes of the N2 and N450 potentials dur-
ing incongruent trials (Li et al., 2017).
While the aforementioned studies demonstrate the
added potential of combining rTMS with neuroimaging
and EEG techniques, the reality is that the vast majority
of rTMS studies to date investigating the PFC do not
have an independent neurophysiological measure of
the impact of stimulation, which limits the cogency
of their conclusions.
Language
Language has been one of the longest studied cognitive
functions using the TMS virtual lesion method. Pascual-
Leone et al. (1991) conducted the first such study in six
 TRANSCRANIAL MAGNETIC STIMULATION
presurgical epilepsy patients. The protocol applied 10-s
trains of high-frequency rTMS while patients were asked
to count aloud. Stimulation was localized to 15 different
targets in perisylvian regions of both hemispheres. When
stimulation was applied to the left but not right inferior
frontal gyrus (Broca’s area), speech arrest suggestive of
transient motor aphasia was observed in all subjects. Intra-
carotid amobarbital testing was also conducted and con-
firmed left hemisphere language dominance in all
subjects. Subsequent TMS studies have largely corrobo-
rated these findings and have attempted to optimize stim-
ulation protocols to improve interstudy variability (Jennum
et al., 1994; Epstein et al., 1996). This line of research has
provided a strong foundation for using TMS for presurgical
mapping of language function. TMS devices for this indi-
cation are FDA approved and will be discussed further in
the section “Part III: Clinical Applications”.
Since Pascual-Leone and colleagues’ landmark study
over 25 years ago, there have been numerous efforts
to further probe the language system using TMS. This
includes critical work identifying the regional func-
tional anatomy of semantic and phonologic processes in
Broca’s area (Devlin et al., 2003; Aziz-Zadeh et al.,
2005; Sakreida et al., 2018), uncovering unexpected con-
nections between speech comprehension, language
knowledge, and motor systems (Watkins et al., 2003;
Berent et al., 2015), and identifying a critical role for the
left inferior frontal gyrus in processing grammar and syn-
tax (Sakai et al., 2002). The latter study by Sakai and col-
leagues exemplifies the potential utility of chronometric
TMS protocols. They eloquently showed that TMS-
induced effects on syntactic processing of sentences only
occurred when stimulation was applied during a specific
time window (150ms after the start of verb presentation).
TMS studies have also contributed to our growing
understanding of how the brain may functionally reorga-
nize after damage (e.g., stroke) to left-sided language
areas. Most notably, this includes: (i) the potential benefit
of recruiting ipsilateral lesional and perilesional cortical
regions and (ii) the potential detriment of increased right
hemispheric activity leading to transcollosal interhemi-
spheric inhibition of the left-sided language areas
(Hamilton et al., 2011). These neurophysiological princi-
ples have been translated to develop novel clinical treat-
ment strategies of TMS for poststroke aphasia and will
be discussed further in the section “Part III: Clinical
Applications”.
Other examples
More abstract social and moral based “frontal lobe” func-
tions have also been cleverly investigated using TMS
methodologies. One of the best examples of this comes
from Knoch and colleagues’ work on reciprocal fairness
83
(Knoch et al., 2006). Reciprocal fairness is the concept of
enforcing social fairness norms through the punishment
of other’s unfair behaviors even if it hurts their own self-
interest (Fehr and Fischbacher, 2003). The Ultimatum
Game can be used to assess reciprocal fairness by eval-
uating the extent to which players reject their bargaining
partner’s unfair offers despite an economic incentive to
accept such offers (G€uth et al., 1982). Knoch and col-
leagues reported that 15 min of low-frequency rTMS
applied to the right, but not left, DLPFC reduced willing-
ness to reject intentionally unfair offers (even though the
subjects still judged them as unfair). Put in other words,
inhibition of the right DLPFC yielded subjects less able
to resist economic temptation and thus were weaker
enforcers of principles of reciprocal fairness. This study
provides evidence for the causal involvement of the right
DLPFC in decision-making surrounding fairness-related
behaviors.
Another interesting example comes from TMS
research investigating the role of the PFC in placebo
responses. A variety of structural and functional neu-
roimaging studies in healthy volunteers have identified
the DLPFC as a critical node in the placebo network.
The majority of these studies have focused on placebo
analgesia, but similar findings have been demonstrated
across many placebo paradigms (Stein et al., 2012;
Wager and Atlas, 2015). Further support for the impor-
tant role of the DLPFC came from a longitudinal study
of placebo analgesia in patients with Alzheimer’s
disease (AD) (Benedetti et al., 2006). The rationale
for this study was that cognitively impaired patients
may not have expectations about therapeutic benefits
and thus may have diminished placebo responses. Indeed,
they found that the magnitude of placebo effects nega-
tively correlated with cognitive status but also with pre-
frontal functional connectivity. These studies provide
a strong signal for the role of the PFC in placebo mech-
anisms but are correlative in nature. Krummenacher
and colleagues conducted a TMS placebo analgesia
study aimed at adding direct causal inference to this
evidence base. In this study of 40 healthy volunteers,
half were given the expectation that the TMS device
would yield analgesic effects and half were told that
the device was simply recording data. Both groups
were then given either 15 min of 1-Hz rTMS to right
and left DLPFC or sham stimulation. They found that
active rTMS completely abolished strong placebo
responses (ratings of pain tolerance and pain thresh-
olds) in the group that was given analgesic effect expec-
tation (Krummenacher et al., 2010). Such studies
raise the intriguing possibility of using rTMS with dif-
ferent parameters to possibly enhance placebo response
and thus improve the therapeutic effect of various
interventions.
84 M.J. BURKE ET AL.
PART III: CLINICAL APPLICATIONS
Presurgical mapping
TMS virtual lesion methodologies have been clinically
translated as a novel noninvasive methodology for pre-
surgical motor and language mapping. We will focus
on the example of language mapping to build on themes
discussed earlier in this chapter.
In the surgical management of tumors in or near lan-
guage “eloquent” brain regions (e.g., left-sided inferior
frontal, supramarginal, and superior temporal gyri), neuro-
surgeons must balance the extent of their resection with
the preservation of critical language functions. To evaluate
and optimize considerations prior to the surgery, surgeons
have traditionally used approaches that include fMRI,
PET, EEG, and/or magnetoencephalography (MEG).
More recently, MRI-navigated TMS has been investigated
as a means of directly interrogating language pathways
and adding causal data to preoperative decision-making
algorithms. Similar to previously described neuropsycho-
logic studies, TMS single pulses or rTMS trains can be
delivered to a specific brain region during a language task
(e.g., object naming). If stimulation of the targeted region
results in consistent task impairment (e.g., naming errors)
then one can infer that the region may be necessary for the
patient’s language function and should ideally not be
included in the resection. This process is then repeated
multiple times with different cortical targets (typically
5–10mm apart) until a map of brain coordinates that are
causally implicated and not implicated is produced
(Lioumis et al., 2012; Tarapore et al., 2013).
TMS presurgical mapping has been shown to correlate
well with the gold standard of intraoperative direct cortical
stimulation and may offer superior accuracy to presurgical
fMRI and MEG (Krieg et al., 2012; Picht et al., 2013;
Tarapore et al., 2013). There is also evidence suggesting
that TMS mapping may improve patient outcomes by
optimizing patient selection, allowing for larger safe resec-
tions with smaller craniotomies and reducing long-term
neurologic deficits (Frey et al., 2014; Sollmann et al.,
2015). Currently, the Nexstim eXimia Navigated Brain
System TMS device has been cleared by the FDA
for motor and language mapping and its clinical use is
rapidly expanding.
Diagnostic biomarkers
One of the primary goals of investigating TMS cortical
excitability and plasticity paradigms has been to try to
develop neurophysiological signatures of different brain
diseases. Many disorders in neurology and psychiatry
lack objective biomarkers, which can result in challeng-
ing clinical diagnoses, heterogeneity in clinical trial
enrollment, and difficulty quantifying response to
treatments. The clinical applications of TMS biomarkers
are still in their infancy but recently there have been large
strides toward reaching this objective.
AD has been one focus of such efforts and implicates
many of the neurophysiological measures described in
the section “Part I: Basis and Technological Principles
of TMS” (Freitas et al., 2011). First, patients with mild
and moderate AD often present with lower RMTs, as evi-
dence of cortical hyperexcitability (Cantone et al., 2014).
The exact mechanism underpinning this increased excit-
ability is debated but some studies suggest that it may
parallel early disease progression (Ferreri et al., 2011).
Interestingly, in end-stage AD, RMT can increase, creat-
ing an overall bimodal distribution. This latter observa-
tion may be related to the burden of cortical neuronal
loss and atrophy (Perretti et al., 1996). In an early study
of SICI in AD patients, Liepert and colleagues found
reduced SICI compared with healthy controls, and the
level of reduction correlated with dementia severity
(Liepert et al., 2001). However, these findings have been
inconsistently replicated (Di Lazzaro et al., 2004). Per-
haps a more robust TMS measure in AD is SAI, in which
multiple studies have shown more consistent alterations
in cortical excitability (Freitas et al., 2011; Cantone et al.,
2014). As previously described, SAI mechanisms are
believed to reflect central cholinergic activity and thus
these findings support a model of cholinergic deficit in
AD patients. This is further strengthened by findings that
cholinesterase inhibitors increase SAI in AD patients
(Di Lazzaro et al., 2002, 2005). SAI has also been found
to be significantly reduced in amnestic MCI patients but
not in nonamnestic MCI patients (Nardone et al., 2012).
Accordingly, Nardone and colleagues suggest that SAI
may predict the progression to AD, but this requires fur-
ther study and corroboration. Other single- or paired-
pulse TMS measures such as LICI, ICF, and cortical
silent period have not yielded reliable abnormalities in
AD (Freitas et al., 2011; Cantone et al., 2014). Finally,
changes in rTMS-induced plasticity (i.e., ability of
LTP/LTD-like plasticity responses to be induced) have
also been demonstrated in AD patients. Studies in this
area are relatively limited but preliminary findings sug-
gest that AD patients may have impaired plasticity
responses to both traditional rTMS and theta-burst proto-
cols (Cantone et al., 2014; Fried et al., 2017).
Frontotemporal dementia (FTD) is another relevant
disorder that has been investigated for potential TMS
markers of disease. In contrast to AD, the majority of cor-
tical excitability measures, including RMT and SAI,
have not yielded significant changes. In one study, SICI
was shown to be depressed in FTD patients with the pro-
gressive nonfluent aphasia subtype but was normal in
patients with behavioral variant FTD and semantic
dementia (Burrell et al., 2011). Patients with FTD do
 TRANSCRANIAL MAGNETIC STIMULATION
show consistent depression of a variety of nonspecific
TMS measures assessing the integrity of central motor
circuits, such as reduced MEP amplitude, increased
MEP latency, and increased corticomotor conduction
times (Burrell et al., 2011). This complements lines of
research suggesting that FTD may have subclinical
motor dysfunction and shared pathophysiological mech-
anisms with motor neuron diseases such as ALS.
A recent study conducted by Benussi and colleagues
aimed to consolidate much of the data presented earlier to
see if AD could be reliably distinguished from FTD
based on a panel of TMS neurophysiological measures
(Benussi et al., 2017). They compared RMT, SICI,
ICF, LICI, and SAI in 79 patients with AD, 64 patients
with FTD (22 patients with primary progressive aphasia
and 42 with behavioral variant), and 32 healthy controls.
They found significant impairment of SAI among
AD patients and significant impairment of combined
SICI/ICF in FTD patients. Receiver operating character-
istic curve analyses revealed that TMS markers differen-
tiated FTD from AD with a sensitivity of 91.8% and
specificity of 88.6%, AD from healthy controls with a
sensitivity of 84.8% and specificity of 90.6%, and
FTD from healthy controls with a sensitivity of 90.2%
and specificity of 78.1%. These results highlight the
potential clinical utility of TMS as a noninvasive diag-
nostic biomarker in cognitive neurology practice.
Briefly, TMS neurophysiological measures are also
being actively studied as biomarkers for a variety of other
neurologic and psychiatric conditions outside of the
focus of this chapter and this book. Most notably,
single- and paired-pulse TMS “threshold tracking” has
been shown to be a robust early marker of upper motor
neuron dysfunction in patients with ALS (Menon
et al., 2015). ALS can be a challenging diagnosis to make
(particularly with respect to identifying upper motor neu-
ron signs), and thus TMS techniques are rapidly being
adopted in ALS clinical settings and in research trials.
Other areas of ongoing TMS biomarker research include
epilepsy (de Goede et al., 2016), autism (Uzunova et al.,
2016), multiple sclerosis (Simpson and Macdonell,
2015), schizophrenia (Hasan et al., 2013), and a variety
of movement disorders (e.g., Parkinson’s disease, pro-
gressive supranuclear palsy, multiple system atrophy,
and Huntington’s disease) (Vucic and Kiernan, 2017).
Treatment of medication-resistant
depression
The ability of rTMS to noninvasively modulate target
brain regions has been translated to provide new treat-
ment strategies for a variety of neurologic and psychiatric
disorders (Lefaucheur et al., 2014). Currently, the most-
recognized therapeutic indication is medication-resistant
85
depression (Brunoni et al., 2017). The main goal of this
TMS clinical application is to increase excitability of
the left DLPFC as a means to modulate activity both
locally and throughout its connected neural network. This
is based on two fundamental principles: (i) in most patients
with depression, the left DLPFC has been shown to be
hypoactive and hypometabolic on functional neuroimag-
ing studies (Baxter et al., 1989; Fitzgerald et al., 2006) and
(ii) clinical improvement with antidepressant pharmaco-
therapies has been associated with increased activity of
the left DLPFC (Mayberg et al., 2000). The first controlled
clinical trial on the use of rTMS for medication-resistant
depression was published in 1996 (Pascual-Leone et al.,
1996) and revealed the laterality of the effects and the
dependency on the specific rTMS protocol. The most
commonly used protocol involves high-frequency (e.g.,
10-Hz) rTMS applied to the left DLPFC for 37.5 min,
5 days per week over 4–6 weeks (Lefaucheur et al.,
2014). However, a recent randomized, multicenter, clini-
cal noninferiority trial has shown that intermittent theta
burst applied to the left DLPFC may achieve equivalent
efficacy to the traditional rTMS protocol and can be con-
ducted in a fraction of the time (average 3 min/session)
(Blumberger et al., 2018). Though more work is needed
to corroborate Blumberger and colleagues’ findings,
these results are consistent with data discussed in the
section “Part I: Basis and Technological Principles of
TMS” regarding theta burst’s potential ability to more
rapidly and efficiently induce synaptic long-term poten-
tiation (Suppa et al., 2016). Other stimulation targets and
protocols exist, such as low-frequency rTMS to the right
DLPFC; however, the evidence supporting their effi-
cacy is less robust (Lefaucheur et al., 2014).
In addition to the clinical efficacy demonstrated in
clinical trials, rTMS for depression has also been found
to have real-world clinical effectiveness (George et al.,
2013) and cost effectiveness (Nguyen and Gordon,
2015). To date, the FDA has cleared six different TMS
devices for medication-resistant depression and insur-
ance companies in many countries around the world
now cover the cost of treatments.
Treatment of AD
Large-scale research efforts are actively investigating
many other therapeutic applications of TMS with frontal
lobe targets. AD has been studied over the past 5–10
years and preliminary results are promising. In one ran-
domized three-arm pilot study of patients with mild-to-
moderate AD, 20-Hz rTMS applied to the left and right
DLPFC was found to improve cognitive function when
compared to low-frequency TMS and sham stimulation
groups. Significant improvements were observed on all
outcome measures (Mini Mental Status Examination,
86 M.J. BURKE ET AL.
Instrumental Daily Living Activity scale, and Geriatric
Depression Scale) and were assessed at 1 and 3 months
(Ahmed et al., 2012). However, another sham-controlled
study with a similar 20-Hz rTMS protocol (applied only
to the left DLPFC) did not find any significant improve-
ments in memory or executive functions but did report
significant improvement in sentence comprehension
(Cotelli et al., 2011).
There is also a line of TMS AD research that combines
TMS with cognitive training (rTMS-COG). This proto-
col consists of 10-Hz rTMS that targets six different brain
regions believed to be implicated in AD. During the stim-
ulation, patients receive concurrent cognitive training
targeting the function of the corresponding brain region.
The six regions include: right and left DLPFC (working
memory, judgment, and executive functions), Broca’s
and Wernicke’s areas (language production and percep-
tion, respectively), and right and left parietal somatosen-
sory association cortex (spatial/topographical orientation
and praxis). The treatments occur for 1 h daily, five
sessions/week for 6 weeks, followed by biweekly ses-
sions for 3 months. After a positive open-label proof-
of-concept study (Bentwich et al., 2011), Rabey and
colleagues completed a small randomized, double-blind,
sham-controlled study of the rTMS-COG intervention.
They reported significant improvements on their primary
outcome of Alzheimer’s Disease Assessment Scale-
Cognitive Subscale (ADAS-Cog) and also found their
protocol to be safe and well tolerated (Rabey et al.,
2013). A large, pivotal, premarket approval study of
rTMS-COG has been completed but the results are cur-
rently awaiting publication.
Treatment of stroke
Stroke rehabilitation for aphasia and motor weakness is
another exciting area of translational TMS research. After
stroke, a variety of neuroplastic changes occurs that may
lead to decreased excitability of lesioned/perilesional
brain regions and increased excitability of the homotopic
regions in the contralateral hemisphere (Cicinelli et al.,
2003). This imbalance is believed to be maladaptive
and primarily mediated by abnormally increased interhe-
mispheric inhibition from the unaffected to the affected
side (Ferbert et al., 1992; Shimizu et al., 2002). TMS
stroke rehabilitation strategies aim to restore this disequi-
librium via two main approaches: (i) increase cortical
excitability of the affected hemisphere (for example,
using high-frequency rTMS) or (ii) decrease cortical
excitability of the contralateral hemisphere (for exam-
ple, using low-frequency TMS) (Fregni and Pascual-
Leone, 2007).
For poststroke aphasia, both ipsilateral (Holland
et al., 2011) and contralateral (Barwood et al., 2011;
Weiduschat et al., 2011) stimulation strategies have
shown benefit in small pilot studies. The latter approach
has been further evaluated by a randomized sham-
controlled trial that aimed to relate clinical effects to
brain imaging activation patterns (Thiel et al., 2013).
This study enrolled 24 right-handed, subacute ischemic
stroke patients with left MCA infarctions and clinically
documented aphasia. The treatment protocol consisted
of 10 days of daily 20-min sessions of low-frequency
1-Hz rTMS over the right posterior inferior frontal gyrus
combined with 45 min of poststimulation speech and lan-
guage therapy. Comparing rTMS to the sham group, they
reported significant improvements in language perfor-
mance on their primary outcome of the Aachen Aphasia
Test score. They also conducted pre/post-PET scans and
found that patients in the rTMS group activated propor-
tionally more voxels in left hemisphere language net-
works after treatment compared with sham group
patients. Based on these findings, a large multicenter trial
of this combined TMS and speech-language therapy pro-
tocol is currently underway (NORTHSTAR trial). Given
the scope of this book, we have focused on poststroke
aphasia; however, it should be noted that rTMS treatment
trials of motor recovery after stroke have also been quite
promising (Hsu et al., 2012; Du et al., 2016) and trials are
ongoing.
Other neurologic and psychiatric treatments
The list of potential TMS applications in neurology and
psychiatry is lengthy and rapidly expanding month by
month. A comprehensive review and evidence-based
guidelines of all major applications have been provided
in a consensus statement of European TMS experts
(Lefaucheur et al., 2014). Briefly, additional indications
with prefrontal targets include addiction (right/left
DLPFC), obsessive–compulsive disorder (left orbito-
frontal cortex), anorexia nervosa (left DLPFC), negative
symptoms of schizophrenia (right/left DLPFC), and
posttraumatic stress disorder (right DLPFC). Outside
of the PFC, other major fields of TMS therapeutic
research include chronic pain (motor cortex), movement
disorders (motor cortex, premotor/supplementary motor
cortices), auditory hallucinations in schizophrenia (left
temporal–parietal cortex), epilepsy (targeted to epilepto-
genic focus), and migraine (occipital cortex). With
regards to the latter, the eNeura single-pulse TMS device
has recently received FDA approval for migraine acute
abortive therapy (Lipton et al., 2010) and as a daily pre-
ventative treatment (Starling et al., 2018).
Conclusions and future directions
TMS is a noninvasive brain stimulation technology
that has provided extensive contributions toward better
 TRANSCRANIAL MAGNETIC STIMULATION
understanding frontal lobe functions and relevant
brain–behavior relationships. TMS is increasingly being
translated for use in clinical settings and represents a
promising new treatment approach for many complex
neurologic and psychiatric disorders that currently have
limited treatment options. However, we need to empha-
size that, aside from depression, most of the therapeutic
indications discussed in this chapter have yet to have
devices cleared by the FDA for on-label use. As such,
their use remains restricted to off-label and experimental
investigational research.
We also must point out that there are still many unan-
swered questions regarding TMS mechanisms of action.
This includes mechanisms at the cellular/neuronal level
as discussed in the section “Part I: Basis and Technological
Principles of TMS”, but also relates to therapeutic mech-
anisms at the clinical trial level. With respect to the latter,
there is a clear need to better understand the degree of indi-
vidual variability in the physiological effects of TMS and
the nature and magnitude of TMS’s placebo effects. TMS
exemplifies an innovative and elaborate device technol-
ogy that may induce high therapeutic expectations and
yield enhanced placebo effects (e.g., compared to oral pill
treatments) (Kaptchuk et al., 2000). How to properly inter-
pret efficacy in this context and how to delineate the rel-
ative importance of treatment-specific effects vs placebo
effects is challenging. This is particularly difficult given
the growing body of literature providing strong evidence
that placebos themselves are capable of meaningfully and
relevantly modulating brain networks (Benedetti, 2014).
Most of the placebo-focused work in the TMS field has
concentrated on developing optimal sham devices to
ensure adequate blinding in placebo-controlled studies.
However, there is a relative paucity of research investigat-
ing the bigger-picture questions posed here, which may
need to be probed with specialized study designs such
as additional “no treatment” control arms (Wager and
Atlas, 2015).
Another major issue that will need to be tackled going
forward involves the potential ethical implications sur-
rounding new therapeutic applications of TMS. Most rel-
evant to the readership of this book would be the example
of TMS for cognitive enhancement. This topic is quite
controversial and there is mixed evidence surrounding
the potential ability of TMS to meaningfully enhance
speed and/or accuracy of cognitive processes in healthy
individuals (Luber and Lisanby, 2014). However, regard-
less of the level of evidence, people are and will continue
to use these technologies for this purpose and this
requires careful analysis from ethical and public policy
perspectives.
Finally, as has been highlighted throughout this chap-
ter, the technological aspects of TMS are constantly and
rapidly evolving. On the horizon are many innovations
87
that could dramatically improve future TMS-based
research. These innovations can generally be split into
two major categories: (i) refinement of existing technol-
ogy, such as new TMS-EEG analysis techniques and
new TMS navigation tools integrated with functional
connectivity and (ii) new technologies that are currently
in the process of being translated to humans from animal
studies, such as TMS microcoils (Park et al., 2013)
and noninvasive deep-brain stimulation techniques
(Lozano, 2017). These and other advances will undoubt-
edly accelerate the ongoing efforts investigating brain–
behavior causality, diagnostic biomarkers, and clinical
treatments.
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FURTHER READING
Ziemann U (2017). Thirty years of transcranial magnetic stim-
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