646707

research-article2016
NROXXX10.1177/1073858416646707The NeuroscientistLewis et al.

Review
The Neuroscientist

Brain Neuromodulation
116
The Author(s) 2016
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DOI: 10.1177/1073858416646707
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Philip M. Lewis1,2,3, Richard H. Thomson3,4,

Jeffrey V. Rosenfeld1,2,3,5, and Paul B. Fitzgerald3,4

Abstract
The modulation of brain function via the application of weak direct current was first observed directly in the early
19th century. In the past 3 decades, transcranial magnetic stimulation and deep brain stimulation have undergone
clinical translation, offering alternatives to pharmacological treatment of neurological and neuropsychiatric disorders.
Further development of novel neuromodulation techniques employing ultrasound, micro-scale magnetic fields and
optogenetics is being propelled by a rapidly improving understanding of the clinical and experimental applications
of artificially stimulating or depressing brain activity in human health and disease. With the current rapid growth in
neuromodulation technologies and applications, it is timely to review the genesis of the field and the current state of
the art in this area.

Keywords
neuromodulation, neuropsychiatry, cognitive, implant, bionics, brain

Introduction and blindness (Lewis and others 2015). Stimulation of

A variety of techniques have been developed, or are
under investigation, for influencing or modulating the
activity of the human brain. This development is being
propelled by rapid growth in our understanding of the
clinical and experimental applications of artificially
stimulating or depressing brain activity in human
health and disease. Brain stimulation is being applied
clinically for the treatment of a variety of neurological
conditions (for review, see Udupa and Chen 2015)
including Parkinsons disease (Benabid and others
1987; Odekerken and others 2016), essential tremor
(Baizabal-Carvallo and others 2014; Benabid and oth-
ers 1991), chronic pain (Boccard and others 2014), and
epilepsy (Fisher and others 2010). Brain stimulation is
also finding applications in neuropsychiatry, now
available as a treatment option in the management of
severe medication-resistant depression (Fitzgerald
2013) and obsessive-compulsive disorder (Greenberg
and others 2010). Experimentally, electrical stimula-
tion of the brain is being investigated in a neuropsychi-
atric context as a novel treatment for autism (Enticott
and others 2014), schizophrenia (Fitzgerald and others
2008), addiction (Amiaz and others 2009), and anorexia
nervosa (McClelland and others 2016), while it is also
under investigation for the treatment of sensory defi-
cits including neural deafness (Otto and others 2008)
the somatosensory cortex is also being explored as a
means of providing sensory feedback to recipients of
motor neuroprostheses, offering the potential to pro-
vide a sense of touch to robotic limbs (Berg and oth-
ers 2013).
Techniques for brain stimulation or neuromodulation
vary depending on the clinical context, the precise loca-
tion and size of targeted areas, and the desired effect.
With the current rapid growth in neuromodulation tech-
nologies and applications, it is timely to review the gen-
esis of the field and the current practice in this area. We
conclude with a brief comment on future directions.
1
Department of Neurosurgery, Alfred Hospital, Melbourne, Victoria,
Australia
2
Department of Surgery, Central Clinical School, Monash University,
Clayton, Victoria, Australia
3
Monash Institute of Medical Engineering, Monash University, Clayton,
Victoria, Australia
4
Monash Alfred Psychiatry Research Centre, Central Clinical School,
Monash University, Melbourne, Victoria, Australia
5
F. Edward Hbert School of Medicine, Uniformed Services University
of the Health Sciences, Bethesda, MD, USA
Corresponding Author:
Philip M. Lewis, Department of Surgery, Central Clinical School,
Monash University, Level 6 Alfred Centre, Clayton, Victoria, Australia.
Email: philip.lewis@monash.edu

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2 The Neuroscientist
Figure 1. A patient of Aldinis receiving treatment, with the
electrical circuit completed by the patients hand touching the
base of the Voltaic pile. Image reproduced from Aldini (1803).
The Evolution of Brain Stimulation
Direct Electrical Stimulation
Electricity has occupied a place in the therapeutic arma-
mentarium of clinicians for the past two millennia, includ-
ing for the treatment of conditions involving the head.
Indeed, Scribonius Largus, physician to the Roman
Emperor Tiberius, used electric shocks to the forehead,
administered by the electric torpedo fish, to treat headache
in the first century AD (Baldwin 1992). Fast-forwarding
to the 17th and 18th centuries, newly developed static
electricity generation and electrochemical charge-storage
devices allowed extensive experimentation with and, ulti-
mately, the widespread use of electricity as a therapeutic
tool (Priestley 1767). The discovery by Galvani that
nerves and muscles were electrically excitable (Piccolino
1997) led to Volta developing the first electrochemical
battery while investigating Galvanis theory of animal
electricity (Piccolino 2000). Galvanis nephew Aldini
later carried out numerous studies on the effects of elec-
tricity, or galvanism on the human body, during which he
also investigated its therapeutic potential (Parent 2004). In
1803, Aldini described the successful treatment of a
patient with severe melancholy by electrical stimulation
of the head (Aldini 1803) (Fig. 1).
In his 1819 book written in English, Aldini further out-
lined his thoughts on the therapeutic potential of galva-
nism, stating that it will be beneficial to apply the
galvanic fluid, as a mechanical stimulant in diseases
where an excitement of the nervous and muscular system
is necessary (Aldini 1819, p. 61).
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In particular, Aldini recommended electrical stimula-
tion of the brain for cases of melancholy madness,
apoplexy, and even syncope, in the belief that
. . . in these maladies, the brain, being particularly affected,
may probably, by this means, be re-established in the regular
use of its functions. (Aldini 1819, p. 65)
Throughout the 19th century, the use of electricity as a
therapeutic tool in neuropsychiatry became established
(Gilman 2008), and its ready availability in the laboratory
setting facilitated the resolution of the long-standing
debate on cortical functional localization (Fritsch and
Hitzig 1870). The use of electrical stimulation for map-
ping brain function continued into the 20th century, par-
ticularly by Penfield, who did extensive studies of brain
stimulation on patients undergoing surgical excision of
epileptic foci (Penfield 1947). However, toward the end
of the 19th century noninvasive brain stimulation for
treating psychiatric illness began to fall out of favor
(Gilman 2008).
This trend was reversed in the 1930s when Cerletti
popularized electroconvulsive therapy (ECT; Fig. 2).
After initial success in treating a patient with schizophre-
nia (Accornero 1988), Cerletti expanded the scope of his
treatments to include patients with mania and severe
depression, after which the technique became popular.
While Cerletti used a 90-V direct current pulse to induce
a seizure in his first patient (Accornero 1988), modern
ECT employs alternating current of varying frequencies,
applied to one or both hemispheres.
Lower intensity noninvasive brain stimulation or
brain polarization (Priori and others 1998) continued to
be used throughout the early to mid-20th century for the
treatment of insomnia in a technique referred to as elec-
trosleep (Nias 1976). This involved delivering short
pulses of weak DC current across the temples; notably,
unlike ECT electrosleep did not induce seizures. In 1998,
Priori etal confirmed that low-intensity brain polariza-
tion alters cortical excitability, prompting further investi-
gation into its applications in neurology. The technique,
contemporaneously referred to as transcranial direct cur-
rent stimulation (tDCS), is currently being investigated in
a variety of neurological contexts, including but not lim-
ited to, improving cognitive performance (Floel 2014),
treating depression (Brunoni and others 2013) and
enhancing motor recovery after brain injury (Liew and
others 2014).
The application of invasive brain stimulation to the
treatment of neurological disorders began in earnest in the
1950s, particularly after the development of stereotactic
methods for accurately placing electrodes deep within the
brain substance (Spiegel and others 1947). From the 1950s
to the 1970s, a number of groups investigated deep brain
Lewis et al. 3
Figure 2. Cerletti and Binis first electroshock device on display
in the Museum of the History of Medicine, University of Rome,
Italy. Image Francesco Pallone, reproduced with permission
under the terms of Creative Commons Licence CC-BY-SA-3.0
from Wikimedia Commons. (https://commons.wikimedia.org/
wiki/File:Macchina_elettroshock_Ugo_Cerletti.jpg).
stimulation (DBS) for the treatment or diagnosis of psy-
chiatric (Delgado and others 1952) and movement disor-
ders (Bekhtereva and others 1963; Sem-Jacobsen 1966),
epilepsy (Cooper 1978), and chronic pain (Hosobuchi and
others 1973). The demonstrated effectiveness, reversibil-
ity and lower morbidity of DBS for Parkinsonian tremor
as compared with lesional surgery (Benabid and others
1991) has led to its subsequent uptake as a surgical treat-
ment of choice for this condition. DBS continues to be
explored as a therapeutic option in a variety of other con-
ditions, discussed in further detail later.
In parallel with the development of DBS, stimulation
of the cortex for the treatment of neurological dysfunc-
tion was being actively explored. For example, visual
cortex stimulation, which was known to reproducibly
elicit small visual percepts or phosphenes (Penfield
1947), was investigated from the late 1950s onward as a
means of providing functional visual perception to the
blind (Lewis and others 2015).
The therapeutic applications of cortical stimulation
were extended in 1991 with the discovery that epidural
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stimulation of the precentral gyrus (i.e., motor cortex)
could provide symptomatic relief for patients with central
pain (Brown 2001). Cortical stimulation is now also per-
formed therapeutically for tinnitus, depression and post-
stroke motor rehabilitation (Tronnier and Rasche 2013).
Of particular interest is the development of closed-loop,
or responsive neuromodulation systems for the auto-
mated termination of epileptic seizures, a technology
which also holds promise for the unattended treatment of
medically refractory major depression (Sun and Morrell
2014).
Neurostimulation of somatosensory and visual corti-
ces with neuroprosthetics continues to progress in the
experimental setting, however full clinical translation of
this research is yet to be achieved.
Magnetic Stimulation
Two decades after Fritsch and Hitzig used direct electri-
cal stimulation of the exposed cortex to map the canine
motor cortex, dArsonval demonstrated that the same
principles of electromagnetic induction Faraday had
exploited to generate electricity, could stimulate neural
tissue without requiring any physical connection to the
target. Notably, this discovery was made while dArsonval
was investigating the ability of high-strength alternating
magnetic fields to induce heating in living animals
(Geddes 1999). Volunteers placed inside the coil reported
seeing phosphenes, experiencing vertigo and occasion-
ally syncope (Geddes 1999).
DArsonval published in French, therefore his work
was largely overlooked by English and German research-
ers. Beer (1902) independently designed a similar device
for treating depression, however it was not widely used.
Thompson (1910) also developed a stimulating coil large
enough to fit a human head, which was capable of induc-
ing sensations of light and taste. Despite others develop-
ing similar devices (Barlow and others 1947; Dunlap
1911; Magnusson and Stevens 1911), techniques for and
applications of magnetic brain stimulation did not signifi-
cantly advance for the greater part of the 20th century.
Transcranial Magnetic Stimulation.The first transcranial
magnetic stimulation (TMS) device capable of evoking
cortical activity was developed by Barker and colleagues
(Barker and others 1985) (Fig. 3). Reports of its potential
in neuropsychiatry quickly followed, with a number of
studies suggesting a role for TMS in clinical depression
(George and others 1995; Grisaru and others 1994;
Hoflich and others 1993; Kolbinger and others 1995;
Pascual-Leone and others 1996). Extensive research in
the period since has resulted in the application of both
conventional suprathreshold TMS and more recently,
low-intensity TMS for the investigation and treatment of
4 The Neuroscientist
Figure 3. Image of Barker and colleagues first transcranial
magnetic stimulation (TMS) device. Reproduced from Barker
and others (1985), with permission.
a wide variety of neurological conditions, with the most
widely studied indication being treatment-resistant major
depressive disorder.
Contemporary Neuromodulation
Techniques
Established
Implanted Forms of Direct Electrical Stimulation.Despite
its long history of use in medicine, the precise mecha-
nisms underlying the efficacy of direct (i.e., invasive)
electrical brain stimulation remain the subject of ongo-
ing investigation. From a biophysical standpoint, the
electrical and structural inhomogeneity of brain tissue,
particularly the variable directionality and excitability of
axons, dendrites, and neuronal somata render accurate
modeling of the effects of applied electric fields on brain
tissue a challenging task (Meffin and others 2014;
Miranda and others 2007). Notwithstanding these uncer-
tainties about stimulation of bulk brain tissue, the funda-
mental effects of externally applied electric fields on
individual neurons are well described. By placing a neg-
atively or positively charged electrode directly over or
among the target neurons, those in the vicinity of the
electrode become hyper- or depolarized, due to the
combined influence of electronic current flow and altera-
tions in the conductance of membrane-bound, voltage-
sensitive ion channels (Fig. 4; Brocker and Grill 2013).
This results in the suppression or elicitation respectively,
of action potentials in neuronal elements close to the
electrode(s). Hyperpolarization in the vicinity of an elec-
trode can also produce depolarization and subsequent
neuronal activation distant to the electrode via virtual
cathodes, resulting in anodic stimulation if the depolar-
ization reaches threshold. Stimulation proximal to a
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physical cathode is therefore referred to as cathodic
stimulation (Brocker and Grill 2013).
Beyond the direct activation of neurons by the applica-
tion of electric fields, modulation and/or propagation of
the stimulus can occur through trans-synaptic mecha-
nisms, which may be excitatory or inhibitory in nature.
The relative contributions of both factors to the spread of
activation and the behavioral manifestations of cortical
stimulation remains the subject of some debate (Histed
and others 2013; Tehovnik and Slocum 2013).
Epidural and Subdural Cortical Stimulation. Stimulation of
the cortical surface can be achieved by placing electrodes
on the dura (epidurally), or directly on the cortex itself
(subdurally). Both methods have been applied in a variety
of neurological conditions including chronic pain (Lefau-
cheur and others 2009; Tsubokawa and others 1991),
movement disorders (Moro and others 2011; Woolsey
and others 1979), tinnitus (De Ridder and others 2007),
medically refractory partial seizures (Bergey and others
2015), and for the treatment of depression (Hajcak and
others 2010). Reported stimulation sites include motor
cortex, Heschls gyrus, speech areas, and the dorsolateral
prefrontal cortex (Tronnier and Rasche 2013).
Cortical stimulation is commonly used by neurosur-
geons during awake craniotomy to identify sensorimotor
cortex and speech areas (Hervey-Jumper and others
2015), while subcortical stimulation is increasingly used
to avoid damage to deeper motor pathways during sur-
gery for glioma resection (Schucht and others 2013).
Epidural electrode placement forces electrical charge
to flow through the dura and cerebrospinal fluid before
reaching the cortex, which reduces stimulus focality and
increases stimulus thresholds relative to subdural elec-
trodes (Bezard and others 1999; Kim and others 2011).
Indeed, computational modeling studies have shown that
50% or less of the total current output during epidural
cortical stimulation (ECS) reaches the cortex, with the
bulk of the remainder shunted through cerebrospinal fluid
(CSF; Kim and others 2011; Manola and others 2005;
Wongsarnpigoon and Grill 2008). In patients with corti-
cal atrophy, the problem of current shunting is magnified
by the increased volume of CSF between the electrode
and the cortical surface, which limits the utility of ECS in
these patients (Tronnier and Rasche 2013).
While subdural electrodes therefore offer the advan-
tage of more focal stimuli at lower currents, the requisite
opening of the dura increases the risk of both CSF
leak and infection. Moreover, the threshold intensity for
stimulus-induced seizures is expectedly lower for subdu-
ral electrodes (Bezard and others 1999).
Intracortical Stimulation.Intracortical electrodes were
investigated in the 1960s, as a means with which to
Lewis et al. 5

Figure 4. Illustration depicting cathodic versus anodic monopolar stimulation. During cathodic stimulation (A, left), current is
drawn from the axon of a neuron proximal to the electrode, resulting in depolarization. This results in current being drawn into
the axon from surrounding tissue distant to the electrode, hyperpolarizing the axon membrane and creating virtual anodes
at these sites. Note however that the strength of hyperpolarization at the virtual anodes is much weaker (approximately 5
times less) than the depolarization proximal to the electrode (cathode). Thus, during anodic stimulation (B, right), the same
phenomenon occurring in reverse results in remote depolarization at virtual cathodes. Given the lower amplitude of
depolarization at the virtual cathodes, a greater stimulus strength is required for this to result in neuronal firing. Note that the
electrodes depicted contain multiple electrodes, thus stimulation could be performed in a bipolar fashion, with one electrode
acting as the cathode, with the other as the anode. Figure adapted from Brocker and Grill (2013), with permission.

selectively stimulate small populations of neurons and at
lower stimulation currents (Doty 1965; Stoney and others
1968). Smaller electrodes that penetrate the cortical sur-
face also reveal laminar variations in behavioral responses
(motor and sensory) and stimulus thresholds, which can
vary substantially between the cortical surface (layer I)
and layer V (Koivuniemi and others 2011; Tehovnik and
others 2003). The underlying principles of intracortical
microstimulation (ICMS) are common to that of epidural
and subdural stimulation; however, the electrodes are
much smaller and are usually insulated, with a small area
of exposed electrode material through which stimulus
current is delivered (the stimulating surface). This surface
may be at or offset from the electrode tip (Fig. 5), and
may have physical dimensions similar in scale to a single
pyramidal cell body (i.e., <100 m; Wang and others
2013).
This fact, combined with laminar variations in neu-
ronal architecture and connectivity throughout the cor-
tex renders both the population of neurons stimulated
(Fig. 6), and thus the behavioral consequences of
ICMS, very sensitive to small changes in electrode
position (Overstreet and others 2013).
A drawback to the penetration of cortical tissue
required for ICMS is the host response to the indwelling
foreign body, which can result in a fibrous (Woolley and
others 2013) and/or glial (Polikov and others 2005;
Woolley and others 2013) encapsulation of the electrodes.
This glial scar separates the electrode from viable neu-
rons and increases the impedance of the electrodetissue
interface, although it may resolve over a period of months
(Wang and others 2013). Future novel electrode designs
may mitigate this phenomenon (Lewis and others 2015).
Deep Brain Stimulation.Deep brain stimulation (DBS)
involves the stereotactic implantation of lead-mounted
electrodes (Fig. 7) into deeper brain structures implicated
in the genesis of neurological disease. A large number of
stimulation targets have been identified with the choice
of target dependent on the underlying condition; how-
ever, there remains uncertainty about the most effective
target for many of the conditions treated with DBS. Com-
mon targets in the treatment of movement disorders such
as Parkinsons disease, essential tremor, and dystonia
include the subthalamic nucleus, globus pallidus inter-
nus, and the ventral intermediate nucleus of the thalamus

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6 The Neuroscientist

Figure 5. Scanning electron micrograph of two intracortical microelectrode designs, the left (a), showing the conventional
arrangement of an exposed electrode tip through which stimulus current is delivered. The novel design on the right (b)
incorporates a 70-m length annulus of exposed electrode material, located approximately 500 m from the insulated electrode
tip. Figure 5a adapted from (Normann and others 1999), with permission. Figure 5b supplied courtesy of the Monash Vision
Group.

(Baizabal-Carvallo and others 2014; Odekerken and oth-
ers 2016; Pouclet-Courtemanche and others 2016). Con-
versely, DBS for obsessive compulsive disorder may
target the anterior limb of the internal capsule, nucleus
accumbens or the inferior thalamic peduncle (Greenberg
and others 2010; Jimenez-Ponce and others 2009). For a
complete list of disorders and corresponding stimulation
targets, the reader is referred to the recent review by
(Udupa and Chen 2015).
The precise mechanisms by which DBS exerts its ther-
apeutic effect are still being determined; however, there is
growing recognition that the influence of DBS on brain
networks, of which the chosen targets form a component,
is key to clinical efficacy (Alhourani and others 2015).
Importantly, these networks are formed not only from
fibers projecting directly to and from stimulation targets
and other brain regions but also from fibers of passage,
being axons in the vicinity of the target but that do not
synapse directly with it (Agnesi and others 2013). Given
the structural and behavioral complexity of these net-
works, the task of determining precisely how DBS
achieves its therapeutic effect is a formidable one indeed.
As mentioned briefly earlier, DBS electrodes are typi-
cally implanted using stereotactic systems, ensuring pre-
cise placement within deep targets that may be very
small; in the case of the ventrointermediate nucleus, the
anteroposterior and mediolateral dimensions may be as
small as 2 4 mm, respectively (Vassal and others 2012).
Current-generation DBS electrodes are typically quad-
ripolar in design (Fig. 8), allowing for precise configura-
tion of stimulation site, focality, and polarity (Marks
2015). Further refinements may be realized through the
development of DBS leads that incorporate smaller and
greater numbers of electrodes, allowing for a more
nuanced and targeted approach to stimulation.
Transcranial Magnetic Stimulation. As described earlier, the
basic principles of magnetic neurostimulation derive
from Faradays experiments in the early 1830s, which
demonstrated that an alternating current in a primary cir-
cuit will induce the same in an isolated secondary circuit
if the two are in close proximity. During TMS, a signifi-
cant electrical charge is stored in capacitors, which is
periodically discharged through conducting coils to pro-
duce a time-varying magnetic field. This magnetic field
induces an electric field in the brain, which itself consti-
tutes an electrically conductive medium analogous to a
wire. Thus current flow occurs in the brain, which if suf-
ficiently strong, will depolarise neurons in the tissue
located just under the coil.
TMS can be used to noninvasively stimulate neural
tissue due to the lack of resistance to the passage of a
magnetic field across tissue including the skull. The mag-
netic field strength, however, is significantly reduced in
relationship to the distance between the stimulating target
and the magnetic source, requiring a very strong (>1
tesla) field strength at the face of the coil.
Commercially available TMS devices typically pro-
duce two pulse types: a biphasic pulse or a monophasic
pulse, with a third variation called the half-sine pulse
(Fig. 9). A biphasic pulse is approximately sinusoidal and
is generally of shorter duration than a monophasic pulse,
which involves a rapid rise to peak values, followed by a
slow decay back to zero. In commercially available

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Lewis et al. 7
Figure 6. The results of a computational modeling study,
showing the total number of cells recruited by an intracortical
electrode advanced through each cortical layer (A, top) and
the percentage of total neuronal recruitment accounted
for by pyramidal neurons (B, bottom), as stimulus strength
is increased. This demonstrates that increasing stimulus
strength not only increases the volume of tissue stimulated,
but also alters the distribution of neuronal subtypes activated.
Figure reproduced from (Overstreet and others 2013) with
permission.
stimulators, several types of coils are typically used. These
include circular and figure-of-eight shaped coils. In gen-
eral, figure-of-eight shaped coils produce a stronger more
focussed magnetic field with better spatial resolution of
activation compared to circular coils (Ueno and others
1988). Considerable development is now occurring of a
range of deeper brain stimulation coils capable of provid-
ing TMS to a range of brain targets, not just on the cortical
surface.
Repetitive transcranial magnetic stimulation (rTMS)
involves applying TMS stimulation pulses repetitively to
the cortex, usually at a fixed stimulation frequency
(Wassermann 1998). rTMS can either activate or inhibit
cortical activity depending on stimulation frequency
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(Fitzgerald and others 2006). The classical observation
has been that low frequency (~1 Hz) stimulation for a
period of 15 minutes or longer induces a transient inhibi-
tion, or a decrease in activity, of the cortex (Chen and
others 1997), whereas stimulation at frequencies above 1
Hz has been shown to induce increased cortical activation
(Siebner and others 2000). The mechanisms underlying
such inhibition remain unclear although there are simi-
larities to long-term depression, a cellular experimental
phenomenon wherein repeated low frequency stimulation
reduces activity in individual synapses (Chen and others
1997). Conversely, some authors suggest that the
increased cortical activity in response to higher-frequency
rTMS may be due to a transient increase in the efficacy of
excitatory synapses (Pascual-Leone and others 1994),
analogous to the cellular phenomena of long-term poten-
tiation. Importantly, others have shown that the individ-
ual variations in response to rTMS can be significant;
indeed, some study subjects show an inverse response
(i.e., decreasing cortical excitability) to increasing rTMS
frequency, or even demonstrate no frequency dependence
at all (Hamada and others 2013; Maeda and others 2000).
Attempts to improve the efficacy of TMS have resulted
in the development of more complex rTMS stimulus pat-
terns that more closely mimic intrinsic patterns of neuro-
nal firing. For example, theta burst stimulation (TBS),
which involves the application of short-duration high-
frequency 50-Hz trains at 5 Hz or theta frequency, has
been shown to induce cortical plasticity in a much shorter
timeframe compared to conventional rTMS (Huang and
others 2005). Notably however, the aforementioned indi-
vidual variability in response to rTMS has also been seen
in studies of TBS (Hamada and others 2013).
Stimulating at high frequencies has also been shown to
produce transient functional lesions in cortical areas
receiving stimulation (Flitman and others 1998; Pascual-
Leone and others 1991). Therefore, rTMS may be used as
a neurophysiological probe to test the functional integrity
of different cortical regions by either activating these
regions or inhibiting them.
The greatest area of application for rTMS techniques
currently is in the treatment of neuropsychiatric disor-
ders. A robust series of studies has demonstrated that
rTMS has significant therapeutic benefit in the treatment
of major depressive disorder. Studies have demonstrated
the efficacy of both high frequency stimulation applied to
the left dorsolateral prefrontal cortex and low frequency
stimulation applied to the right dorsolateral prefrontal
cortex (Berlim and others 2013; Berlim and others 2014;
Fitzgerald and others 2003; Fitzgerald and Daskalakis
2011; George and others 2010; OReardon and others
2007). This body of research has led to the translation of
rTMS into clinical practice where it is now approved for
use, and increasingly used in clinical practice in a
8 The Neuroscientist

Figure 7. (a) Coronal magnetic resonance imaging (MRI) showing bilateral deep-brain stimulation electrodes, implanted for the
treatment of Parkinsons disease. (b) Chest radiograph showing typical placement of the subcutaneously implanted stimulator
hardware.

application of a low-amplitude (1-2 mA) DC to the brain

Figure 8. An example of a quadripolar, or four-electrode,
deep brain stimulation (DBS) lead. All rights reserved. Used
with the permission of Medtronic.
growing number of countries. Research continues to
explore the potential therapeutic benefit of rTMS in a
number of other disorders, including obsessive compul-
sive disorder, schizophrenia, posttraumatic stress disor-
der, chronic pain, and substance abuse (Fitzgerald 2011).
Transcranial Direct Current Stimulation. Transcranial direct
current stimulation (tDCS) is a method for modifying
the behavior of neurons and/or neuronal networks using
nondepolarizing electrical current. It involves the
through two surface electrodes placed on the scalp (Paulus
2003). In the most commonly used method, electrode pads
covered with sponges are connected to a low-voltage
stimulation device. Stimulation is usually applied continu-
ally for a period of time, commonly between 15 and 20
minutes.
Since the resurgence of interest in the application of
tDCS in late 1990s, a series of neurophysiological studies
have demonstrated the capacity of tDCS to modulate brain
activity, opening its use to wider experimental and clinical
applications (Bikson and others 2012; Liebetanz and oth-
ers 2002; Nitsche and others 2003). Studies have demon-
strated that there are effects on cortical excitability under
both the stimulating anode (positive electrode) and cathode
(negative electrode) that are divergent in polarity; typi-
cally, an increase in cortical excitability is seen under the
anode, and a decrease under the cathode (Paulus 2003).
While this polarity model might be useful for predicting
response in a general sense, it may be overly simplistic.
Exposure of neurons to weak DC current influences neuro-
nal behavior through a complex milieu of short- and long-
term effects at a local and regional level. These include the
aforementioned simple alterations in neuronal firing pat-
terns and cortical excitability that occur in a polarity-
dependent manner (the somatic doctrine; Bikson and
others 2012), as well as other synaptically mediated
changes that themselves are implicated in the observed
longer term effects of tDCS on cortical excitability, net-
work behavior and thus neuronal plasticity. (Bikson and
others 2012; Stagg and Nitsche 2011). From a clinical
standpoint, it has been shown that the response rate to
tDCS may only be as high as 50% (Wiethoff and others

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Lewis et al. 9
Figure 9. Typical transcranial magnetic stimulation (TMS) pulse shapes. (a) Monophasic pulse. (b) Half-sine pulse. (c) Biphasic
pulse. Reproduced from Sommer and others (2006), with permission.
2014). Clearly more research is required to better under-
stand the demographic and neurophysiological factors that
predict the likely response to stimulation.
Notwithstanding the uncertainty surrounding individ-
ual responses, the ability of tDCS to modulate brain func-
tion in an excitatory or inhibitory direction in a noninvasive
fashion has led to its rapid expansion as a tool in cognitive
neuroscience. Stimulation may be applied during or prior
to the performance of a cognitive task as a way of tempo-
rarily enhancing or inhibiting performance. Studies have
demonstrated that single sessions of tDCS can produce
transient improvement in a range of cognitive functions,
for example, working memory (Hoy and others 2013);
however, these improvements are limited in healthy con-
trols compared with patients (Hoy and others 2013).
Research is now exploring whether these benefits can be
applied in longer treatment paradigms in disorders such as
Alzheimers disease and schizophrenia. With regards to
the use of tDCS for cognitive enhancement in healthy
individuals, aside from questions of efficacy there are a
myriad of ethical considerations yet to be fully addressed.
Noteworthy is that a recent survey of tDCS researchers
highlighted significant concerns about safety and misuse
of tDCS by nonexperts (Riggall and others 2015).
Other potential applications of tDCS in neuropsychia-
try include the treatment of depression; parallel to the
situation with rTMS, the greatest body of research is
focused on the use of tDCS to modulate mood. To date a
series of relatively small studies have explored the effects
of tDCS in clinical depression. These were recently sum-
marized in a meta-analysis, which suggests that tDCS has
antidepressant efficacy, but that further research is
required to allow adequate translation of this into clinical
practice (Shiozawa and others 2014).
Other Noninvasive Electrical Stimulation Approaches.
Although often confused with tDCS, there are a number
of other forms of noninvasive electrical stimulation used
to potentially modulate cortical excitability. During
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tDCS, a direct nonvarying current is typically applied at a
single stimulation intensity. It remains unclear whether
this is the most efficient way of inducing changes in corti-
cal excitability with scalp administered electrical stimu-
lation, and a variety of alternative approaches are under
investigation. For example, during intermittent DCS, the
stimulation pulse is interrupted periodically at a specific
interval and frequency (transcranial pulsed current stimu-
lation (Fitzgerald 2014; Jaberzadeh and others 2014)). Ini-
tial research with this approach suggests that it might have
greater effects on corticospinal excitability when applied
to the motor cortex than standard tDCS (Jaberzadeh and
others 2014). The second approach with a fixed stimula-
tion frequency is transcranial alternating current stimula-
tion (tACS). tACS uses an alternating current, centered
either on zero or with a current offset. tACS is an attrac-
tive brain stimulation approach as it can be potentially
applied at a frequency relevant to modulating intrinsic
neural oscillations (Frohlich 2014) although it is not clear
whether this always will result in enhanced effects on
brain activity (Brignani and others 2013). A third variant
of electrical stimulation is the application of transcranial
random noise stimulation (tRNS) where electrical activity
is modulated in a random fashion (potentially to overcome
homoeostatic responses to externally applied current).
tRNS can be used to alter cortical excitability (Terney and
others 2008) and its application in the treatment of schizo-
phrenia is being explored (Palm and others 2013).
Novel Neuromodulation Techniques
A variety of novel neuromodulation techniques are cur-
rently being developed that show promise as future meth-
ods of choice, depending on the application.
Low-Intensity Magnetic Fields.Chance observations of
improved mood after magnetic resonance imaging (MRI)
scanning in depressed patients participating in a medica-
tion trial, led to a formal investigation of the phenomenon
10 The Neuroscientist

Figure 10. (a) Commercially available, 500-m-diameter microcoil used to successfully stimulate retinal ganglion cells
magnetically. (b) The same coil after removal of insulation, showing the copper wires. (c) Computer simulation showing the
electric field distribution around a model of the same coil. Figure adapted from Bonmassar and others (2012), with permission.

by Rohan and others (2004). The authors of that study
found that, despite the relatively weak intracranial elec-
tric field induced by the MRI (0.7 V/m during MRI vs
1-500 V/m for rTMS), 77% of the study subjects who
underwent MRI reported improved mood. In contrast,
only 30% of subjects who received a sham MRI reported
mood improvement (Rohan and others 2004). These find-
ings led to further investigation into what was subse-
quently termed low-field magnetic stimulation (LFMS),
in a double-blind, randomized, sham-controlled study of
the mood-improving effects of LFMS in depressed
patients. Using a custom-built, tabletop LFMS device to
deliver the stimuli, the authors earlier findings were
reproduced in the larger cohort (n = 63), with significant
improvements in mood seen in LFMS-treated subjects
compared with controls (Rohan and others 2014).
In a similar fashion, transcranial pulsed electromag-
netic fields (T-PEMF), adapted from its use in osteoar-
thritis treatment, also induces low-intensity subthreshold
electric fields in brain tissue (0.22 V/m) but employs a
different waveform to LFMS (Martiny and others 2010).
The technique has also shown efficacy for the treatment
of depression in double-blind, randomized controlled tri-
als (Martiny and others 2010; Straaso and others 2014).
Further refinements to low-field magnetic stimulation
techniques may be possible by synchronizing stimulus
waveforms to the recipients individual alpha frequency,
as determined by EEG (Leuchter and others 2015). By
targeting the resonant frequency of a particular cortical
circuit, it may be possible to stimulate and/or entrain
these circuits using much lower energy than conventional
suprathreshold TMS techniques (Leuchter and others
2015).
Another alternative to dynamic techniques such as
rTMS is static field stimulation, with several authors
demonstrating modulation of brain activity using fields
one-tenth the strength of TMS (Gonzalez-Rosa and oth-
ers 2015; Oliviero and others 2011).
Micromagnetic Stimulation.Micromagnetic stimulation
refers to the generation of very small alternating mag-
netic fields to stimulate neuronal firing, with the stimulat-
ing device implanted within or close to the relevant neural
target. While the fundamental principles are the same as
TMS, the efficacy of micromagnetic stimulation of neural
tissue was only very recently demonstrated (Bonmassar
and others 2012; Park and others 2013) (Fig. 10). Park
and colleagues demonstrated that stimulation of the audi-
tory nucleus in a hamster could be achieved using a com-
mercially-available microcoil 600 m in length, excited
with a 300-mV, 50-s pulse. The advantages of reducing
the scale of a magnetic stimulation device are clear: A
reduction in the volume of stimulated tissue will offer
improved selectivity and potentially treatment efficacy.
Moreover, the tissue encapsulation of an implanted
micromagnetic stimulating element should be overcome
by increasing the stimulus strength. Once a steady-state
biological response has been reached, such stimulating
elements should show stable long-term performance.
Magnetic stimulation also demonstrates orientational
selectivity, thereby using multiple such stimulating ele-
ments could permit even further control of the stimula-
tion of fibers with varying orientations.
Unsolved problems with current methods of generat-
ing micromagnetic fields for neuromodulation include
high power consumption (and therefore heat generation),
which may preclude the development of an implantable
device (Luan and others 2014).
Ongoing work in this field may address these prob-
lems, for example using exotic materials to improve the

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Lewis et al. 11
efficiency of magnetic stimulation, as recently demon-
strated by Guduru and others (2015). The authors of that
study administered 10 g of 30-nm-diameter magneto-
electric particles into the tail vein of a mouse, forcing
them to cross the blood-brain barrier using a strong,
externally applied static magnetic field. The nanoparti-
cles reduced the strength of the external magnetic field
required to modulate neural activity by 2 orders of mag-
nitude (Guduru and others 2015). A significant drawback
to micromagnetic stimulation is the need for cranial sur-
gery to perform hardware implantation. It remains to be
seen whether or not the risks of surgery will be out-
weighed by the efficacy of such stimulation when com-
pared against alternative noninvasive techniques currently
under development.
Ultrasound. Ultrasound is emerging as a promising tech-
nology for highly spatially focused, noninvasive neuro-
modulation. The excitation of peripheral nerves by
ultrasound was first observed by Harvey (1929). Later
studies confirmed that focused ultrasound (FUS) could
modulate the activity of mammalian brain tissue in vitro
(Rinaldi and others 1991) and in vivo (Fry and others
1958; Velling and Shklyaruk 1988). More recent work
has shown alterations in human sensory evoked EEG
responses during exposure to transcranial FUS (tFUS;
Legon and others 2014), and the possibility of using tFUS
as a diagnostic or therapeutic tool in neurology and/or
neuropsychiatry is being actively explored.
Unlike very high-powered tFUS, which exploits the
thermal effects of ultrasound to ablate tissue, low-powered
or nonthermal tFUS for modulation of neural activity is
thought to act via the mechanical effects of ultrasound on
nerve membranes (Tyler 2011). These effects include
cavitation-induced cyclic deformation (expansion and con-
traction) of the neuronal cell membranes (Krasovitski and
others 2011; Tyler 2011), acoustic pressure-induced mem-
brane deformation and fluid disturbances such as microjets
or streaming (Tyler 2011).
Ultrasound-induced neuromodulation has been
achieved at a wide range of frequencies, however Tufail
etal (2011) recommend frequencies between 0.2 and 0.7
MHz, offering the best compromise between spatial
selectivity, tissue absorption and penetration of the intact
skull (Tufail and others 2011). Notably however, one
group reported that brain exposure to 8 MHz ultrasound
through the frontal bone can affect mood in humans
(Hameroff and others 2013). An important consideration
in this context is the fact that the long-term effects of non-
thermal tFUS are as yet unknown.
Optogenetic Techniques. Optogenetic neuromodulation is a
promising technique wherein spatially and temporally
precise activation or inhibition of neural circuitry can be
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achieved using light. This ability is conferred by the deliv-
ery into a host organism of genes expressing for light-
sensitive ion channels called opsins, of which rhodopsin is
one that has been studied extensively (Boyden and others
2005; Zemelman and others 2002). The development of
technology to support optogenetic neuromodulation is
progressing rapidly (Lee and others 2015), however sig-
nificant challenges remain before the technique will see
translation into clinical practice. Williams and Denison
(2013) summarized these challenges, which include the
development of techniques for safe delivery and integra-
tion of opsins into the target tissue, increasing the sensitiv-
ity of opsins to achieve low-power stimulation and
integrating the light delivery hardware with the target tis-
sue in a durable manner. The recent development of flex-
ible, thin microprobes incorporating light-emitting diodes
and microfluidic channels may represent a significant step
forward in achieving this goal (Jeong and others 2015).
Summary and Outlook
The development of techniques for influencing the activ-
ity of the human brain is occurring rapidly, with clinical
translation well underway. Further work in this field will
not only refine existing techniques but also reveal new
methods for modulating the behavior of neural circuitry
with improved spatial, temporal, and functional selectiv-
ity, possibly requiring a multimodal approach. With con-
temporary technology, significant improvements in the
treatment of neurological and neuropsychiatric disease
have already been realized, beyond that achievable using
purely pharmaceutical means. Further developments in
this field will undoubtedly translate to superior clinical
efficacy and an even more widespread adoption of neuro-
modulation technologies in human health and disease.
Authors Note
Jeffrey V. Rosenfeld and Paul B. Fitzgerald are joint senior authors.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this arti-
cle: PBF has received equipment for research from Medtronic
Ltd, Magventure A/S, and Brainsway Ltd and funding for
research from Cervel Neurotech.
References
Accornero F. 1988. An eyewitness account of the discovery of
electroshock. Convuls Ther 4(1):409.
12 The Neuroscientist
Agnesi F, Johnson MD, Vitek JL. 2013. Deep brain stimulation:
how does it work? Handb Clin Neurol 116:3954.
Aldini J. 1803. An account of the late improvements in galva-
nism. London: Wiles & Taylor. 254 p.
Aldini J. 1819. General views on the application of galvanism
to medical purposes. London, England: W. Clowes. 105 p.
Alhourani A, McDowell MM, Randazzo MJ, Wozny TA,
Kondylis ED, Lipski WJ, and others. 2015. Network effects
of deep brain stimulation. J Neurophysiol 114(4):210517.
Amiaz R, Levy D, Vainiger D, Grunhaus L, Zangen A. 2009.
Repeated high-frequency transcranial magnetic stimulation
over the dorsolateral prefrontal cortex reduces cigarette
craving and consumption. Addiction 104(4):65360.
Baizabal-Carvallo JF, Kagnoff MN, Jimenez-Shahed J, Fekete
R, Jankovic J. 2014. The safety and efficacy of thalamic
deep brain stimulation in essential tremor: 10 years and
beyond. J Neurol Neurosurg Psychiatry 85(5):56772.
Baldwin B. 1992. The career and work of Scribonius Largus.
Rheinisches Museum fr Philologie 135(1):7482.
Barker AT, Jalinous R, Freeston IL. 1985. Non-invasive
magnetic stimulation of human motor cortex. Lancet
1(8437):11067.
Barlow HB, Kohn HL, Walsh EG. 1947. Visual sensations
aroused by magnetic fields. Am J Physiol 148:3725.
Beer B. 1902. Ueber das Auftraten einer objective
Lichtempfindung in magnetischen Felde. Klin Wochenschr
15:1089.
Bekhtereva NP, Grachev KV, Orlova AN, Latsuk SL. 1963.
Utilization of multiple electrodes implanted in the sub-
cortical structure of the human brain for the treatment of
hyperkinesis [in Russian]. Zh Nevropatol Psikhiatr Im S S
Korsakova 63:38.
Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM,
Hommel M, and others. 1991. Long-term suppression of
tremor by chronic stimulation of the ventral intermediate
thalamic nucleus. Lancet 337(8738):4036.
Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J.
1987. Combined (thalamotomy and stimulation) stereo-
tactic surgery of the VIM thalamic nucleus for bilateral
Parkinson disease. Appl Neurophysiol 50(1-6):3446.
Berg JA, Dammann JF 3rd, Tenore FV, Tabot GA, Boback JL,
Manfredi LR, and others. 2013. Behavioral demonstration
of a somatosensory neuroprosthesis. IEEE Trans Neural
Syst Rehabil Eng 21(3):5007.
Bergey GK, Morrell MJ, Mizrahi EM, Goldman A, King-
Stephens D, Nair D, and others. 2015. Long-term treatment
with responsive brain stimulation in adults with refractory
partial seizures. Neurology 84(8):8107.
Berlim MT, van den Eynde F, Daskalakis ZJ. 2013. Clinically
meaningful efficacy and acceptability of low-frequency
repetitive transcranial magnetic stimulation (rTMS) for
treating primary major depression: a meta-analysis of
randomized, double-blind and sham-controlled trials.
Neuropsychopharmacology 38(4):54351.
Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis
ZJ. 2014. Response, remission and drop-out rates following
high-frequency repetitive transcranial magnetic stimulation
(rTMS) for treating major depression: a systematic review
Downloaded from nro.sagepub.com at INST DE FISIOLOGIA CELU LAR on May 22, 2016
and meta-analysis of randomized, double-blind and sham-
controlled trials. Psychol Med 44(2):22539.
Bezard E, Boraud T, Nguyen JP, Velasco F, Keravel Y, Gross
C. 1999. Cortical stimulation and epileptic seizure: a study
of the potential risk in primates. Neurosurgery 45(2):
34650.
Bikson M, Reato D, Rahman A. 2012. Cellular and network
effects of transcranial direct current stimulation. In: Rossini
PM, editor. Transcranial brain stimulation. Boca Raton,
FL: CRC Press. p 5591.
Boccard SG, Fitzgerald JJ, Pereira EA, Moir L, Van Hartevelt
TJ, Kringelbach ML, and others. 2014. Targeting the affec-
tive component of chronic pain: a case series of deep brain
stimulation of the anterior cingulate cortex. Neurosurgery
74(6):62835.
Bonmassar G, Lee SW, Freeman DK, Polasek M, Fried SI, Gale
JT. 2012. Microscopic magnetic stimulation of neural tis-
sue. Nat Commun 3:921.
Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. 2005.
Millisecond-timescale, genetically targeted optical control
of neural activity. Nat Neurosci 8(9):12638.
Brignani D, Ruzzoli M, Mauri P, Miniussi C. 2013. Is transcra-
nial alternating current stimulation effective in modulating
brain oscillations? PLoS One 8(2):e56589.
Brocker DT, Grill WM. 2013. Principles of electrical stimula-
tion of neural tissue. Handb Clin Neurol 116:318.
Brown JA. 2001. Motor cortex stimulation. Neurosurg Focus
11(3):E5.
Brunoni AR, Valiengo L, Baccaro A, Zanao TA, de Oliveira
JF, Goulart A, and others. 2013. The sertraline vs. electri-
cal current therapy for treating depression clinical study:
results from a factorial, randomized, controlled trial. JAMA
Psychiatry 70(4):38391.
Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM,
Hallett M, and others. 1997. Depression of motor cortex
excitability by low-frequency transcranial magnetic stimu-
lation. Neurology 48(5):1398403.
Cooper IS. 1978. Cerebellar stimulation in man. New York,
NY:Raven Press.
De Ridder D, De Mulder G, Verstraeten E, Seidman M, Elisevich
K, Sunaert S, and others. 2007. Auditory cortex stimulation
for tinnitus. Acta Neurochir Suppl 97(Pt 2):45162.
Delgado JMR, Hamlin H, Chapman WP. 1952. Technique
of intracranial electrode implacement for recording and
stimulation and its possible therapeutic value in psychotic
patients. Confinia Neurol 12(56):3159.
Doty RW. 1965. Conditioned reflexes elicited by electri-
cal stimulation of the brain in macaques. J Neurophysiol
28:62340.
Dunlap K. 1911. Visual sensations from the alternating mag-
netic field. Science 33:6871.
Enticott PG, Fitzgibbon BM, Kennedy HA, Arnold SL, Elliot
D, Peachey A, and others. 2014. A double-blind, random-
ized trial of deep repetitive transcranial magnetic stimula-
tion (rTMS) for autism spectrum disorder. Brain Stimul
7(2):20611.
Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, and
others. 2010. Electrical stimulation of the anterior nucleus
Lewis et al. 13
of thalamus for treatment of refractory epilepsy. Epilepsia
51(5):899908.
Fitzgerald PB. 2011. The emerging use of brain stimulation
treatments for psychiatric disorders. Aust N Z J Psychiatry
45(11):92338.
Fitzgerald PB. 2013. Non-pharmacological biological treatment
approaches to difficult-to-treat depression. Med J Aust
199(6 Suppl):S4851.
Fitzgerald PB. 2014. Transcranial pulsed current stimulation: a
new way forward? Clin Neurophysiol 125(2):2179.
Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De
Castella A, Kulkarni J. 2003. Transcranial magnetic stimu-
lation in the treatment of depression: a double-blind, pla-
cebo-controlled trial. Arch Gen Psychiatry 60(10):10028.
Fitzgerald PB, Daskalakis ZJ. 2011. The effects of repeti-
tive transcranial magnetic stimulation in the treatment of
depression. Expert Rev Med Devices 8(1):8595.
Fitzgerald PB, Fountain S, Daskalakis ZJ. 2006. A comprehen-
sive review of the effects of rTMS on motor cortical excit-
ability and inhibition. Clin Neurophysiol 117(12):258496.
Fitzgerald PB, Herring S, Hoy K, McQueen S, Segrave R,
Kulkarni J, and others. 2008. A study of the effectiveness
of bilateral transcranial magnetic stimulation in the treat-
ment of the negative symptoms of schizophrenia. Brain
Stimul 1(1):2732.
Flitman SS, Grafman J, Wassermann EM, Cooper V, OGrady
J, Pascual-Leone A, and others. 1998. Linguistic process-
ing during repetitive transcranial magnetic stimulation.
Neurology 50(1):17581.
Floel A. 2014. tDCS-enhanced motor and cognitive function in
neurological diseases. Neuroimage 85(Pt 3):93447.
Fritsch G, Hitzig E. 1870. Electric excitability of the cerebrum
(Crump T, Lama S, Trans.). Epilepsy Behav 15(2):12330.
Frohlich F. 2014. Endogenous and exogenous electric fields as
modifiers of brain activity: rational design of noninvasive
brain stimulation with transcranial alternating current stim-
ulation. Dialogues Clin Neurosci 16(1):93102.
Fry FJ, Ades HW, Fry WJ. 1958. Production of reversible
changes in the central nervous system by ultrasound.
Science 127(3289):834.
Geddes LA. 1999. Retrospectroscope. dArsonval, physician
and inventor. IEEE Eng Med Biol Mag 18(4):11822.
George MS, Lisanby SH, Avery D, McDonald WM, Durkalski
V, Pavlicova M, and others. 2010. Daily left prefrontal
transcranial magnetic stimulation therapy for major depres-
sive disorder: a sham-controlled randomized trial. Arch
Gen Psychiatry 67(5):50716.
George MS, Wassermann EM, Williams WA, Callahan A,
Ketter TA, Basser P, and others. 1995. Daily repetitive
transcranial magnetic stimulation (rTMS) improves mood
in depression. Neuroreport 6(14):18536.
Gilman SL. 2008. Electrotherapy and mental illness: then and
now. Hist Psychiatry 19(75 Pt 3):33957.
Gonzalez-Rosa JJ, Soto-Leon V, Real P, Carrasco-Lopez C,
Foffani G, Strange BA, and others. 2015. Static magnetic
field stimulation over the visual cortex increases alpha
oscillations and slows visual search in humans. J Neurosci
35(24):918293.
Downloaded from nro.sagepub.com at INST DE FISIOLOGIA CELU LAR on May 22, 2016
Greenberg BD, Gabriels LA, Malone DA Jr, Rezai AR, Friehs
GM, Okun MS, and others. 2010. Deep brain stimulation
of the ventral internal capsule/ventral striatum for obses-
sive-compulsive disorder: worldwide experience. Mol
Psychiatry 15(1):6479.
Grisaru N, Yaroslavsky U, Abarbanel JM, Lamberg T, Belmaker
RH. 1994. Transcranial magnetic stimulation in depression
and schizophrenia. Eur Neuropsychopharmacol 4:2878.
Guduru R, Liang P, Hong J, Rodzinski A, Hadjikhani A,
Horstmyer J, and others. 2015. Magnetoelectric spin
on stimulating the brain. Nanomedicine (Lond) 10(13):
205161.
Hajcak G, Anderson BS, Arana A, Borckardt J, Takacs I,
George MS, and others. 2010. Dorsolateral prefrontal
cortex stimulation modulates electrocortical measures of
visual attention: evidence from direct bilateral epidural
cortical stimulation in treatment-resistant mood disorder.
Neuroscience 170(1):2818.
Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC.
2013. The role of interneuron networks in driving human
motor cortical plasticity. Cereb Cortex 23(7):1593605.
Hameroff S, Trakas M, Duffield C, Annabi E, Gerace MB, Boyle
P, and others. 2013. Transcranial ultrasound (TUS) effects
on mental states: a pilot study. Brain Stimul 6(3):40915.
Harvey EN. 1929. The effect of high frequency sound waves
on heart muscle and other irritable tissues. Am J Physiol
91:28490.
Hervey-Jumper SL, Li J, Lau D, Molinaro AM, Perry DW,
Meng L, and others. 2015. Awake craniotomy to maximize
glioma resection: methods and technical nuances over a
27-year period. J Neurosurg 123(2):32539.
Histed MH, Ni AM, Maunsell JH. 2013. Insights into cortical
mechanisms of behavior from microstimulation experi-
ments. Prog Neurobiol 103:11530.
Hoflich G, Kasper S, Hufnagel A, Ruhrmann S, Moller H-J.
1993. Application of transcranial magnetic stimulation in
drug-resistant major depressiona report of two cases.
Hum Psychopharmacol 8:361365.
Hosobuchi Y, Adams JE, Rutkin B. 1973. Chronic thalamic
stimulation for the control of facial anesthesia dolorosa.
Arch Neurol 29(3):15861.
Hoy KE, Emonson MR, Arnold SL, Thomson RH, Daskalakis
ZJ, Fitzgerald PB. 2013. Testing the limits: investigating
the effect of tDCS dose on working memory enhancement
in healthy controls. Neuropsychologia 51(9):177784.
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC.
2005. Theta burst stimulation of the human motor cortex.
Neuron 45(2):2016.
Jaberzadeh S, Bastani A, Zoghi M. 2014. Anodal transcranial
pulsed current stimulation: a novel technique to enhance
corticospinal excitability. Clin Neurophysiol 125(2):
34451.
Jeong JW, McCall JG, Shin G, Zhang Y, Al-Hasani R, Kim
M, and others. 2015. Wireless optofluidic systems for pro-
grammable in vivo pharmacology and optogenetics. Cell
162(3):662-674.
Jimenez-Ponce F, Velasco-Campos F, Castro-Farfan G,
Nicolini H, Velasco AL, Salin-Pascual R, and others. 2009.
14 The Neuroscientist
Preliminary study in patients with obsessive-compulsive
disorder treated with electrical stimulation in the inferior
thalamic peduncle. Neurosurgery 65(6 Suppl):2039.
Kim D, Jun SC, Kim HI. 2011. Computational study of subdu-
ral and epidural cortical stimulation of the motor cortex.
Conf Proc IEEE Eng Med Biol Soc 2011:72269.
Koivuniemi A, Wilks SJ, Woolley AJ, Otto KJ. 2011.
Multimodal, longitudinal assessment of intracortical
microstimulation. Prog Brain Res 194:13144.
Kolbinger HM, Holflich G, Hufnagel A, Moller H-J, Kasper
S. 1995. Transcranial magnetic stimulation (TMS) in
the treatment of major depressiona pilot study. Hum
Psychopharmacol 10:30510.
Krasovitski B, Frenkel V, Shoham S, Kimmel E. 2011.
Intramembrane cavitation as a unifying mechanism for
ultrasound-induced bioeffects. Proc Natl Acad Sci U S A
108(8):325863.
Lee S, Williams P, Braine C, Lin DT, John S, Irazoqui P. 2015.
A miniature, fiber-coupled, wireless, deep-brain opto-
genetic stimulator. IEEE Trans Neural Syst Rehabil Eng
23(4):65564.
Lefaucheur JP, Drouot X, Cunin P, Bruckert R, Lepetit H,
Creange A, and others. 2009. Motor cortex stimulation
for the treatment of refractory peripheral neuropathic pain.
Brain 132(Pt 6):146371.
Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams
A, and others. 2014. Transcranial focused ultrasound
modulates the activity of primary somatosensory cortex in
humans. Nat Neurosci 17(2):3229.
Leuchter AF, Cook IA, Feifel D, Goethe JW, Husain M,
Carpenter LL, and others. 2015. Efficacy and safety of
low-field synchronized transcranial magnetic stimulation
(sTMS) for treatment of major depression. Brain Stimul
8(4):78794.
Lewis PM, Ackland HM, Lowery AJ, Rosenfeld JV. 2015.
Restoration of vision in blind individuals using bionic
devices: a review with a focus on cortical visual prostheses.
Brain Res 1595:5173.
Liebetanz D, Nitsche MA, Tergau F, Paulus W. 2002.
Pharmacological approach to the mechanisms of transcra-
nial DC-stimulation-induced after-effects of human motor
cortex excitability. Brain 125(Pt 10):223847.
Liew SL, Santarnecchi E, Buch ER, Cohen LG. 2014. Non-
invasive brain stimulation in neurorehabilitation: local and
distant effects for motor recovery. Front Hum Neurosci
8:378.
Luan S, Williams I, Nikolic K, Constandinou TG. 2014.
Neuromodulation: present and emerging methods. Front
Neuroeng 7:27.
Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A.
2000. Interindividual variability of the modulatory effects
of repetitive transcranial magnetic stimulation on cortical
excitability. Exp Brain Res 133(4):42530.
Magnusson CE, Stevens HC. 1911. Visual sensations caused
by the changes in the strength of a magnetic field. Am J
Physiol 29:12436.
Manola L, Roelofsen BH, Holsheimer J, Marani E, Geelen J.
2005. Modelling motor cortex stimulation for chronic pain
Downloaded from nro.sagepub.com at INST DE FISIOLOGIA CELU LAR on May 22, 2016
control: electrical potential field, activating functions and
responses of simple nerve fibre models. Med Biol Eng
Comput 43(3):33543.
Marks WJ. 2015. Deep brain stimulation management. New
York, NY: Cambridge University Press.
Martiny K, Lunde M, Bech P. 2010. Transcranial low voltage
pulsed electromagnetic fields in patients with treatment-
resistant depression. Biol Psychiatry 68(2):1639.
McClelland J, Kekic M, Campbell IC, Schmidt U. 2016.
Repetitive transcranial magnetic stimulation (rTMS) treat-
ment in enduring anorexia nervosa: a case series. Eur Eat
Disord Rev 24(2):15763.
Meffin H, Tahayori B, Sergeev EN, Mareels IM, Grayden DB,
Burkitt AN. 2014. Modelling extracellular electrical stimu-
lation: part 3. Derivation and interpretation of neural tissue
equations. J Neural Eng 11(6):065004.
Miranda PC, Correia L, Salvador R, Basser PJ. 2007. Tissue het-
erogeneity as a mechanism for localized neural stimulation
by applied electric fields. Phys Med Biol 52(18):560317.
Moro E, Schwalb JM, Piboolnurak P, Poon YY, Hamani C,
Hung SW, and others. 2011. Unilateral subdural motor
cortex stimulation improves essential tremor but not
Parkinsons disease. Brain 134(Pt 7):2096105.
Nias DK. 1976. Therapeutic effects of low-level direct electri-
cal currents. Psychol Bull 83(5):76673.
Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz
D, Lang N, and others. 2003. Pharmacological modula-
tion of cortical excitability shifts induced by transcranial
direct current stimulation in humans. J Physiol 553(Pt 1):
293301.
Normann RA, Maynard EM, Rousche PJ, Warren DJ. 1999. A
neural interface for a cortical vision prosthesis. Vision Res
39(15):257787.
OReardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg
KE, Nahas Z, and others. 2007. Efficacy and safety of
transcranial magnetic stimulation in the acute treatment of
major depression: a multisite randomized controlled trial.
Biol Psychiatry 62(11):120816.
Odekerken VJ, Boel JA, Schmand BA, de Haan RJ, Figee M,
van den Munckhof P, and others. 2016. GPi vs STN deep
brain stimulation for Parkinson disease: three-year follow-
up. Neurology 86(8):75561.
Oliviero A, Mordillo-Mateos L, Arias P, Panyavin I, Foffani
G, Aguilar J. 2011. Transcranial static magnetic field
stimulation of the human motor cortex. J Physiol 589(Pt
20):494958.
Otto SR, Shannon RV, Wilkinson EP, Hitselberger WE,
McCreery DB, Moore JK, and others. 2008. Audiologic
outcomes with the penetrating electrode auditory brainstem
implant. Otol Neurotol 29(8):114754.
Overstreet CK, Klein JD, Helms Tillery SI. 2013. Computational
modeling of direct neuronal recruitment during intracorti-
cal microstimulation in somatosensory cortex. J Neural
Eng 10(6):066016.
Palm U, Hasan A, Keeser D, Falkai P, Padberg F. 2013.
Transcranial random noise stimulation for the treatment of
negative symptoms in schizophrenia. Schizophr Res 146(1-
3):3723.
Lewis et al. 15
Parent A. 2004. Giovanni Aldini: from animal electricity to
human brain stimulation. Can J Neurol Sci 31(4):57684.
Park HJ, Bonmassar G, Kaltenbach JA, Machado AG, Manzoor
NF, Gale JT. 2013. Activation of the central nervous sys-
tem induced by micro-magnetic stimulation. Nat Commun
4:2463.
Pascual-Leone A, Gates JR, Dhuna A. 1991. Induction of
speech arrest and counting errors with rapid-rate transcra-
nial magnetic stimulation. Neurology 41(5):697702.
Pascual-Leone A, Rubio B, Pallardo F, Catala MD. 1996.
Rapid-rate transcranial magnetic stimulation of left dor-
solateral prefrontal cortex in drug-resistant depression.
Lancet 348(9022):2337.
Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M.
1994. Responses to rapid-rate transcranial magnetic stimu-
lation of the human motor cortex. Brain 117(Pt 4):84758.
Paulus W. 2003. Transcranial direct current stimulation (tDCS).
Suppl Clin Neurophysiol 56:24954.
Penfield W. 1947. Some observations on the cerebral cortex of
man. Proc R Soc Lond B Biol Sci 134(876):32947.
Piccolino M. 1997. Luigi Galvani and animal electricity: two
centuries after the foundation of electrophysiology. Trends
Neurosci 20(10):4438.
Piccolino M. 2000. The bicentennial of the Voltaic battery
(1800-2000): the artificial electric organ. Trends Neurosci
23(4):14751.
Polikov VS, Tresco PA, Reichert WM. 2005. Response of
brain tissue to chronically implanted neural electrodes. J
Neurosci Methods 148(1):118.
Pouclet-Courtemanche H, Rouaud T, Thobois S, Nguyen J-M,
Brefel-Courbon C, Chereau I, and others. 2016. Long-term
efficacy and tolerability of bilateral pallidal stimulation to
treat tardive dyskinesia. Neurology 86(7):6519.
Priestley J. 1767. The history and present state of electricity:
with original experiments. London, England: Printed for
J. Dodsley, J. Johnson and T. Cadell. 503 p.
Priori A, Berardelli A, Rona S, Accornero N, Manfredi M.
1998. Polarization of the human motor cortex through the
scalp. Neuroreport 9(10):225760.
Riggall K, Forlini C, Carter A, Hall W, Weier M, Partridge B,
and others. 2015. Researchers perspectives on scientific
and ethical issues with transcranial direct current stimula-
tion: an international survey. Sci Rep 5:10618.
Rinaldi PC, Jones JP, Reines F, Price LR. 1991. Modification
by focused ultrasound pulses of electrically evoked
responses from an in vitro hippocampal preparation. Brain
Res 558(1):3642.
Rohan M, Parow A, Stoll AL, Demopulos C, Friedman S,
Dager S, and others. 2004. Low-field magnetic stimulation
in bipolar depression using an MRI-based stimulator. Am J
Psychiatry 161(1):938.
Rohan ML, Yamamoto RT, Ravichandran CT, Cayetano KR,
Morales OG, Olson DP, and others. 2014. Rapid mood-
elevating effects of low field magnetic stimulation in
depression. Biol Psychiatry 76(3):18693.
Schucht P, Moritz-Gasser S, Herbet G, Raabe A, Duffau H. 2013.
Subcortical electrostimulation to identify network subserv-
ing motor control. Hum Brain Mapp 34(11):302330.
Downloaded from nro.sagepub.com at INST DE FISIOLOGIA CELU LAR on May 22, 2016
Sem-Jacobsen CW. 1966. Depth-electrographic observa-
tions related to Parkinsons disease. Recording and elec-
trical stimulation in the area around the third ventricle. J
Neurosurg 24(1 Suppl):388-402.
Shiozawa P, Fregni F, Bensenor IM, Lotufo PA, Berlim MT,
Daskalakis JZ, and others. 2014. Transcranial direct current
stimulation for major depression: an updated systematic
review and meta-analysis. Int J Neuropsychopharmacol
17(9):144352.
Siebner HR, Peller M, Willoch F, Minoshima S, Boecker H,
Auer C, and others. 2000. Lasting cortical activation after
repetitive TMS of the motor cortex: a glucose metabolic
study. Neurology 54(4):95663.
Sommer M, Alfaro A, Rummel M, Speck S, Lang N, Tings T,
and others. 2006. Half sine, monophasic and biphasic tran-
scranial magnetic stimulation of the human motor cortex.
Clin Neurophysiol 117(4):83844.
Spiegel EA, Wycis HT, Marks M, Lee AJ. 1947. Stereotaxic
apparatus for operations on the human brain. Science
106(2754):34950.
Stagg CJ, Nitsche MA. 2011. Physiological basis of transcranial
direct current stimulation. Neuroscientist 17(1):3753.
Stoney SD Jr, Thompson WD, Asanuma H. 1968. Excitation
of pyramidal tract cells by intracortical microstimulation:
effective extent of stimulating current. J Neurophysiol
31(5):65969.
Straaso B, Lauritzen L, Lunde M, Vinberg M, Lindberg L,
Larsen ER, and others. 2014. Dose-remission of pulsating
electromagnetic fields as augmentation in therapy-resistant
depression: a randomized, double-blind controlled study.
Acta Neuropsychiatr 26(5):2729.
Sun FT, Morrell MJ. 2014. Closed-loop neurostimulation: the
clinical experience. Neurotherapeutics 11(3):55363.
Tehovnik EJ, Slocum WM. 2013. Two-photon imaging and the
activation of cortical neurons. Neuroscience 245:1225.
Tehovnik EJ, Slocum WM, Schiller PH. 2003. Saccadic eye
movements evoked by microstimulation of striate cortex.
Eur J Neurosci 17(4):8708.
Terney D, Chaieb L, Moliadze V, Antal A, Paulus W. 2008.
Increasing human brain excitability by transcranial
high-frequency random noise stimulation. J Neurosci
28(52):1414755.
Thompson SP. 1910. A physiological effect of an alternating
magnetic field. Proc R Soc London (Biol) B82:396399.
Tronnier V, Rasche D. 2013. Epidural and subdural stimulation.
Handb Clin Neurol 116:34351.
Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama
S. 1991. Chronic motor cortex stimulation for the treatment
of central pain. Acta Neurochir Suppl (Wien) 52:1379.
Tufail Y, Yoshihiro A, Pati S, Li MM, Tyler WJ. 2011.
Ultrasonic neuromodulation by brain stimulation with tran-
scranial ultrasound. Nat Protoc 6(9):145370.
Tyler WJ. 2011. Noninvasive neuromodulation with ultra-
sound? A continuum mechanics hypothesis. Neuroscientist
17(1):2536.
Udupa K, Chen R. 2015. The mechanisms of action of deep
brain stimulation and ideas for the future development.
Prog Neurobiol 133:2749.
16 The Neuroscientist
Ueno S, Tashiro T, Harada K. 1988. Localized stimulation of
neural tissue in the brain by means of a paired configuration
of time-varying magnetic fields. J Appl Phys 64:58624.
Vassal F, Coste J, Derost P, Mendes V, Gabrillargues J, Nuti C,
and others. 2012. Direct stereotactic targeting of the ven-
trointermediate nucleus of the thalamus based on anatomic
1.5-T MRI mapping with a white matter attenuated inver-
sion recovery (WAIR) sequence. Brain Stimul 5(4):62533.
Velling VA, Shklyaruk SP. 1988. Modulation of the functional
state of the brain with the aid of focused ultrasonic action.
Neurosci Behav Physiol 18(5):36975.
Wang C, Brunton E, Haghgooie S, Cassells K, Lowery A,
Rajan R. 2013. Characteristics of electrode impedance and
stimulation efficacy of a chronic cortical implant using
novel annulus electrodes in rat motor cortex. J Neural Eng
10(4):046010.
Wassermann EM. 1998. Risk and safety of repetitive transcra-
nial magnetic stimulation: report and suggested guide-
lines from the International Workshop on the Safety of
Downloaded from nro.sagepub.com at INST DE FISIOLOGIA CELU LAR on May 22, 2016
Repetitive Transcranial Magnetic Stimulation, June 5-7,
1996. Electroencephalogr Clin Neurophysiol 108(1):116.
Wiethoff S, Hamada M, Rothwell JC. 2014. Variability in
response to transcranial direct current stimulation of the
motor cortex. Brain Stimul 7(3):46875.
Williams JC, Denison T. 2013. From optogenetic technologies to
neuromodulation therapies. Sci Transl Med 5(177):177ps6.
Wongsarnpigoon A, Grill WM. 2008. Computational modeling
of epidural cortical stimulation. J Neural Eng 5(4):44354.
Woolley AJ, Desai HA, Otto KJ. 2013. Chronic intracortical
microelectrode arrays induce non-uniform, depth-related
tissue responses. J Neural Eng 10(2):026007.
Woolsey CN, Erickson TC, Gilson WE. 1979. Localization in
somatic sensory and motor areas of human cerebral cortex
as determined by direct recording of evoked potentials and
electrical stimulation. J Neurosurg 51(4):476506.
Zemelman BV, Lee GA, Ng M, Miesenbock G. 2002. Selective
photostimulation of genetically chARGed neurons. Neuron
33(1):1522.