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TRANSCRANIAL DIRECT CURRENT STIMULATION AND NEUROPLASTICITY

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In: Transcranial Direct Current Stimulation (tDCS): Emerging Uses, Safety And
Neurobiological Effects
© 2015 Nova Science Publishers, Inc.

Chapter

TRANSCRANIAL DIRECT CURRENT STIMULATION

AND NEUROPLASTICITY

Joanna Ripoll Rozisky, PhD

Luciana da Conceição Antunes, PhD
Aline Patricia Brietzke, MSc
Ana Cláudia de Sousa, MSc
Wolnei Caumo, PhD

Laboratory of Pain & Neuromodulation,

Hospital de Clinicas de Porto Alegre,
Universidade Federal do Rio Grande do Sul,
Address: Ramiro Barcelos, 2350 – Rio Branco, 90035-903
Porto Alegre, Rio Grande do Sul, Brazil

Corresponding Author:
Joanna Ripoll Rozisky
E-mail: joannarozisky@gmail
 Joanna Ripoll Rozisky et al., 2015

Abstract
Transcranial brain stimulation has received an increased interest among the
scientific community due its capability to modulate cortical excitability, which in
turn modifies brain functions resulting in neuroplastic changes. Specifically,
neuroplastic changes (ie “neuroplasticity”) refers to the ability of neurons or brain
structures to adapt and adjust the nervous system at functional and structural
levels when exposed to new experiences. In particular, transcranial direct current
stimulation (tDCS) has been widely explored for its clinical efficacy, safety,
painlessness, portability, ease of application, low cost, well-tolerated among
patients, and positive clinical results seen within a few weeks. This noninvasive
brain therapy has been used as an adjuvant tool for treating neurological and
psychiatric diseases such as chronic pain, depression, obesity, memory and others.
The basic principle of tDCS is modulating cerebral functions through applying a
weak and direct electric current over the target cortical area. Two electrodes
deliver stimulation: 1) Anode depolarizes the neuronal membrane and 2) Cathode
hyperpolarizes the neuronal membrane. This stimulation is what determines the
modulatory effect of tDCS. Overall, the augmentation of cortical excitability is
induced by anodal tDCS whereas the decrease in cortical excitability is induced
with cathodal tDCS. The direction of current and consequently, the after-effects,
depend on the cortical area where the electrodes are placed. Generally, the
stimulation electrode is placed over the target cortical area and the other on the
contralateral area of the body (eg, the contralateral supraorbital area). In this way,
the putative effect of tDCS is the ability to modify neuronal membrane polarity
and therefore, its resting membrane threshold. In both cases, the electric current
induces a sustainable response in the form of a long-term potentiation (LTP)- or
long-term depression (LTD)-like plasticity. Primarily, tDCS was recognized for
its localized cortical plasticity effects, but clinical and experimental studies have
shown that the electric current also affect and modulate subcortical and deeper
structures that are connected to the stimulated cortical area (Bolzoni et al., 2013a,
2013b, Dasilva et al., 2012). Both LTP and LTD mechanisms induced by tDCS
are complex and several molecules and pathways govern these processes,
including cellular and molecular changes, synthesis of neurotransmitters,
receptors and neurotrophic factors, neuronal remodeling, formation of novel
synapses and birth of new neurons. In this chapter, we will describe how tDCS
promotes neuroplasticity in both a healthy and diseased neuron. Specifically, we
will discuss in detail the cellular/molecular processes and the involved
transmitters/receptors governing both LTP and LTD-like plasticity induced by
both anodal and cathodal tDCS: i) how anodal and cathodal stimulation induces
 Transcranial Direct Current Stimulation and Neuroplasticity 61

modifications on resting membrane threshold; ii) how both currents reach cortical
and subcortical regions and promote changes; ii) the transmitters and receptors
involved in neuronal changes (eg, Glutamate and GABA); iii) the rule of
neurotrophic factors, such as Brain-derived neurotrophic factor in the
neuroplasticity induced by tDCS; iv) techniques used to assess the neuroplasticity
induced by tDCS.
 Joanna Ripoll Rozisky et al., 2015

Introduction
For many years, neuroscientists believed that when neural cells died, the
adult brain was able to compensate by creating new synaptic connections among
surviving neurons since it was believed that the brain was devoid of stem cells
pivotal to the creation of new cells. This “no new neurons” dogma was firstly
described by Santiago Ramón y Cajal (1852-1934) who stated, “In adult centers
the nerve paths are something fixed, ended, immutable. Everything may die,
nothing may be regenerated. It is for science of the future to change, if possible,
this harsh decree” (Cajal, 1959). This dogma was challenged about five decades
ago by some neuroscientists Altman and colleagues, who described the first
evidence of the formation of new neurons from animal experiments using brain
autoradiography technique with the tritiated DNA nucleoside (Altman, 1962;
1963). Another important experiment was described in the 1960s by Raisman,
who perceived an “anatomical reorganization” from experiments with neuropil in
the septal nuclei of adult rats after a selective lesion was induced to distinct axons
that terminate on the neurons in those nuclei (Raisman, 1969). Since then, many
researchers in all parts of the world began to further investigate in an attempt to
unravel the mechanisms of the formation of new neurons.
The term “neuroplasticity” was introduced to define neural morphological
and functional changes in child and adult brains. Neuroplasticity, or brain
plasticity, is the ability of the nervous system to replace dead neurons and to make
adaptive changes in response to new or changing environments. Neuroplasticity
can be maladaptive, as seen in some neurological traumas or neurodegenerative
illnesses such as stroke, Parkinson’s or Alzheimer’s disease; or beneficial
adaptive changes such as learning and memory. It is well known that learning is
the most studied form to induce neuroplasticity. A positive correlation to learning
and memory has been consistently demonstrated by experimental studies where
animals are allocated to an enriched environment to improve social, behavioral
and cognitive interactions. With these experimental models, it is possible to
observe a reduction of stress hormones, creation of new synaptic connections in
the hippocampus and in other brain regions, formation of new neurons (process
called “neurogenesis”) and new glial cells (“gliogenesis”), and an increase of
neural factors such as Brain derived neurotrophic factor (BDNF) (Nilsson et al.,
1999; Gould et al., 1999; van Praag et al., 2000; Novkovic et al., 2015).
Transcranial Direct Current Stimulation (tDCS) has been used for a few years
as a non-pharmacological and non-invasive brain stimulation tool to treat
neurological illnesses and for rehabilitation purposes by inducing neuroplasticity
in different brain areas. However, its basic design and concept was introduced
over 100 years ago when Galvani (1737-1798) explored the effects of electric
current in frog’s cell. He demonstrated that electrical stimulation could induce
muscle contraction by sparking electricity within the nerves themselves, i.e the
 Transcranial Direct Current Stimulation and Neuroplasticity 63

brain is able to generate its own electricity that is then distributed through the
nerves to the muscles (Galvani, 1791). The first clinical evidence of this galvanic
theory started with Giovani Aldini (Galvani’s nephew and assistant) by
demonstrating the efficacy of transcranial current stimulation for the complete
rehabilitation of patients with personality disorders (Aldini, 1804). Apart from the
focus on the discovery of new tools and drugs to treat neurological and
psychiatric diseases, the galvanic current continued to be used just for the
treatment of musculoskeletal disorders and peripheral pain. Earlier this century,
new studies with direct electric stimulation were published and the promise of
tDCS as an efficacious technique of non-invasive brain stimulation and its
neuroplastic mechanisms began to unravel.
Pivotal clinical studies performed by Priori and colleagues (1998) followed by
Nitsche and Paulus (2000) demonstrated that tDCS can modulate cortical
excitability through a weak and direct electrical current delivered by two
electrodes placed over the target cortical area. The type of stimulation delivered
by the electrodes will determine the modulatory effects of tDCS. The anode
depolarizes the neuronal membrane and increases cortical excitability whereas the
cathode hyperpolarizes the neuronal membrane and decreases cortical excitability.
Transcranial electric stimulation was first recognized by its ability to change
neuronal membrane polarity and, thus, by its ability to induce localized cortical
excitability changes. Later, clinical and experimental studies revealed that besides
the local changes in membrane polarity, the direct electrical current can reach and
modulate subcortical and deeper structures that are connected to the stimulated
cortical area (Bolzoni et al., 2013a, 2013b, Dasilva et al., 2012). Since then, other
studies have provided further insight regarding the mechanisms behind the short
and long-term after-effects induced by consecutive use of tDCS. In this way, we
can describe that the putative effect of tDCS is the ability to modify neuronal
membrane polarity and, therefore, its resting membrane threshold thus inducing a
sustainable response in the form of two types of neuroplasticity: long-term
potentiation (LTP)- or long-term depression (LTD).
Nowadays, the clinical use of tDCS has increased as it is a portable device and
easy to manage and transport, cost to use is low; it is well tolerable, painless, and
safe. Importantly, its clinical use has increased because many studies have
demonstrated that this non-invasive technique is efficacious for neurological and
psychiatric diseases, as for example: chronic pain, depression, obesity,
schizophrenia, Parkinson, Alzheimer, and others (Boggio et al., 2009; Brunoni et
al., 2011; Laste et al., 2012; Doruk et al., 2014; Kekic et al., 2014; Gomes et al.,
2015; O'Connell and Wand, 2015). Beside its use for treatment and rehabilitation,
tDCS also has been shown to be useful to improve the ability of learning,
cognition and memory (Carvalho et al., 2015; Rohan et al., 2015).
 Joanna Ripoll Rozisky et al., 2015

This chapter is focused on describing the main cellular and molecular

mechanisms that lead tDCS to induce cortical modulatory short and long-term
effects. Specifically, we will discuss how the electric current reaches the cortical
neurons thus modifying the resting membrane threshold, the biomolecules, and
signaling pathways to induce LTP and LTD plasticity.

Physiological Mechanism of tDCS

The first studies regarding the mechanisms of direct current stimulation dated
back 50 years ago when Lippold and Redfean (1964) demonstrated that a weak
current (50-500mA) applied over the frontal cortical area induces behavioral
changes in healthy subjects, with anodal stimulation increasing alertness, mood
and motor activity; and cathodal stimulation producing quietness and apathy.
Since then, other experiments were performed but no positive results were found.
In the late 1990s, Priori and colleagues demonstrated the first and most significant
evidence of cortical excitability changes induced by tDCS by studying the effects
of a weak current (< 0.5 mA) applied over the motor cortical area. They observed
through transcranial magnetic stimulation that a very small electric current is able
to modify motor-evoked potential (MEP) (for more details see Priori et al., 1998).
Posteriorly, these finding were confirmed by Nitshce and Paulus (2000) by
demonstrating the polarity-effects and cortical excitability changes of anodal and
cathodal tDCS: anodal increasing motor-cortex excitability and MEP amplitude
by about 40% and cathodal decreasing motor-cortex excitability and MEP
amplitude. From these initial set of experiments, other studies have been
performed revealing the main mechanisms underlying short and long-lasting
effects of tDCS.
 Transcranial Direct Current Stimulation and Neuroplasticity 65

Figure 1. Effects of anodal and cathodal on membrane polarization. Figure in the left
represents anodal stimulation of primary motor cortex (M1) and the cathodal electrode is placed
over contralateral supraorbital area. The anodal stimulation depolarizes the neuronal membrane
and enhances M1 excitability. The figure in the right illustrates cathodal electrode over M1 and
anodal over the contralateral supraorbital area. The cathodal stimulation hyperpolarizes the
neuronal membrane and diminish M1 excitability. Overall, the type of stimulation determines the
modulatory effect of tDCS.

Short-lasting effects of tDCS

Before beginning a study, it is fundamental to determine tDCS parameters that

govern the polarity-effects and cortical excitability changes of tDCS:
configuration of electrodes; targeting the cortical area to be stimulated; polarity of
stimulation; intensity of stimulus; duration and the number of sessions.
The target cortical area to be stimulated will depend on the reason of
stimulation. For example, for treating musculoskeletal disorders, the anodal
electrode is generally placed over the motor cortex and the cathodal electrode
over the contralateral supra-orbital area (Chang et al., 2015), whereas the
electrode montage widely used for treating psychiatric diseases is to place the
anodal electrode over the dorsal lateral pre-frontal cortex (DLPFC) and the
 Joanna Ripoll Rozisky et al., 2015

cathodal electrode over the contralateral DLPFC or supra-orbital area (Brunoni et

al., 2011; Powell et al., 2014). As well as the cortical area to be stimulated, the
polarity of the electrode will define the modulatory effects of stimulation. In
contrast to other non-invasive brain stimulation techniques, tDCS does not induce
neuronal firing by suprathreshold neuronal membrane depolarization, but rather
modulates spontaneous neuronal network activity (Nitsche et al.; Priori et al.,
2009). As mentioned above, the anodal electric current enhances the neuronal
excitability while cathodal stimulation diminishes it. Overall, the explanation for
these effects is that both electric currents are able to modify neuronal membrane
resting threshold, where anodal stimulation results in neuronal depolarization and
cathodal stimulation yields the opposite result. In addition, anodal polarization
contributes to hyperpolarization of inhibitory interneurons of superficial layers
and cathodal stimulation has a reverse contribution on these neurons (Nitsche and
Paulus, 2000).
The effects of tDCS during stimulation seem to depend more on the changes
in neuronal membrane potentials rather than the effects on neuronal signaling
pathways. This hypothesis is supported by clinical and animal pharmacological
studies that are widely being used to investigate the mechanism underlying
neuromodulatory effects during and after tDCS. Nitsche et al. (2003)
demonstrated that motor cortex excitability induced by anodal stimulation is
blocked after carbamazepine (voltage-dependent sodium channels blocker) and
diminished after flunarizine (calcium-channel blocker) administration in healthy
human subjects. These findings are similar to those observed by Purpura and
McMurtry in 1965. They observed in animal experiments that the decrease in
excitability induced by cathodal stimulation did not change the ion channel
blockade, indicating that neuronal hyperpolarization is induced by cathodal tDCS.
The main reason for both of these results is that the activities of both channels are
voltage dependent (Holmes et al., 1984; McLean and McDonald, 1986).
Beyond the changes in neuronal resting membrane potential during
electric stimulation, studies have shown that one single session of tDCS is able to
induce effects on neuronal membrane potential that can last for up to 60 minutes
beyond the end of stimulation (Nitsche et al., 2003; Nitsche and Paulus, 2001). In
contrast to the effects during the stimulation, the mechanisms underlying the
“after-effects” of tDCS is attributed not exclusively to the changes of electrical
neuronal membrane potential, i.e. effects in ion-voltage channels, but also to the
changes on N-methyl-d-aspartate (NMDA) and gamma-amino-butyric acid
(GABA) receptors (Liebetanz et al., 2002; Nitsche et al., 2003; Stagg et al., 2009).
Study from Nitsche et al. (2005) demonstrated that tDCS interferes with brain
excitability through modulation of intracortical and corticospinal neurons (Nitsche
et al., 2005; Ardolino et al., 2005), resulting in modulatory effects of NMDA and
GABAergic receptor efficacy. They established that intracortical inhibition is
diminished and facilitation is increased by anodal stimulation, while with cathodal
 Transcranial Direct Current Stimulation and Neuroplasticity 67

stimulation results yield the opposite effect. Both results were observed up to 7
min after tDCS, which is considered as short-lasting effects of tDCS. The
resulting intracortical inhibition or facilitation are of intracortical origin and
reflects excitability of inhibitory and excitatory interneurons. As inhibition is
enhanced and facilitation is diminished by GABAergic and antiglutamatergic
substances, but not influenced by ion channel-blockers (Chen et al. 1997, Liepert
et al. 1997; Ziemann et al. 1996, 1998), they may primarily reflect the activity of
the glutamatergic and GABAergic systems in the motor cortex. This result fits
well with the fact that the after-effects of tDCS as well as intracortical inhibition
and facilitation are at least partly controlled by NMDA receptor activity (Nitsche
et al. 2003b; Ziemann et al. 1998). On the other hand, anodal stimulus during
tDCS is not able to change either intracortical inhibition or facilitation, while
cathodal stimulus is able to decrease facilitation. These results are considered as
intra-tDCS effects. Here, the hypothesis is that the short period of anodal
stimulation is not able to change the NMDA receptor efficacy (Nitsche et al.
2003b), whereas the changes observed during cathodal stimulation may be due to
a slight modulation of NMDA receptor activity even for a short period of
stimulation, which would be more easily detectable for cathodal tDCS because of
the generally more stable effects of this condition as compared with anodal tDCS.
Although the intra and short-lasting effects of anodal and cathodal stimulation
lead to neuromodulatory effects on neuronal membrane potential and on cortical
and subcortical excitability (as intracortical inhibition and facilitation), the long-
lasting effects arise upon involvement of long-term potentiation and long-term
depression plasticity, as well as intracellular and molecular changes with the
contribution of neurotrophic factors. These after-effects will be discussed in the
next topics.

Long-lasting effects of tDCS

Long-term Potentiation and Long-term Depression plasticity

The long-lasting effects of tDCS have been related to the mechanisms that
govern the two types of neuroplasticity: long-term potentiation (LTP) and long-
term depression (LTD). LTP and LTD are terms used in neuroscience to describe
two types of long-lasting modifications of synaptic efficacy. The first
electrophysiological studies describing these neuronal changes were performed in
a rodent hippocampus (Bliss and Lomo, 1973). The results demonstrated that high
frequency stimulation of CA3 hippocampal neurons resulted in a long-lasting
increase in excitatory postsynaptic potential (EPSP) amplitude of CA1 neurons,
that is there was a long-lasting change in the postsynaptic neuronal response to a
subsequent stimulus identical to a stimulus applied before the high-frequency
stimuli. Whereas LTP mediates the persistent strengthening of synapses activity
 Joanna Ripoll Rozisky et al., 2015

emitting a long lasting increase in signal transmission between two neurons, LTD
is an activity-dependent reduction in the efficacy of neuronal synapses lasting
hours or longer following a long patterned stimulus. LTD also can result from
strong synaptic stimulation. It is one of several processes that serve to selectively
weaken specific synapses in order to make constructive use of synaptic
strengthening caused by LTP. This is necessary because if allowed to continue
increasing in strength, synapses would ultimately reach a ceiling level of
efficiency, which would inhibit the encoding of new information.
Both LTP and LTD are mediated by two glutamatergic receptors, NMDA and
alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) (Traynelis, et
al, 2010; Delattre, et al, 2015). AMPA depends on influx of sodium ions (Na+)
resulting in depolarization of the postsynaptic cell, while the NMDA receptor has
a magnesium ion (Mg2+) blocking the receptor channel, but when the postsynaptic
cell is depolarized, the Mg2+ is expelled, allowing influx of Ca2+ on concomitant
glutamate binding. Calcium is a second messenger responsible for many of
intracellular changes underlying LTP and LTD. For example, Ca2+ influx can
activate protein kinases, such Calcium/calmodulin-dependent kinase (CaMK), and
in turn, modulate numerous neuronal signaling pathways culminating to the
transcription, translation, and insertion of new glutamate receptors (Pang et al.,
2010). In a long-term mechanism of LTP, CaKM activate protein cyclic
adenosine monophosphate response element-binding protein (CREB), a
transcription factor that mediates gene transcription, formation of new proteins,
changes in the connectivity between neurons, and ultimately, synaptic plasticity
(Nonaka, 2009). There is formation of a dendritic spines, neuronal protrusions
where the most glutamatergic synapses, essential for plasticity, are located. The
dendritic spines are responsible to create an environment for improved synaptic
communication and activation of the neuron (Engert and Bonhoeffer, 1999). In
contrast to LTP, LTD plasticity occurs when a neuron receives low-frequency
stimulation. LTD activates intracellular phosphatases, enzymes that remove the
phosphate group previously attached by kinases, and culminate with
internalization of glutamate receptors, decreasing the efficacy of synaptic
transmission (Mulkey et al., 1993).
LTP and LTD are considered as mechanism of neuroplasticity that lead to the
long lasting after-effects of anodal and cathodal stimulation, manifested by
changes in brain function and improvement of neurological diseases and
disabilities. Both effects are being investigated in both human and animal study.
Primarily, Liebetanz et al. (2002) demonstrated through pharmacological
experiments that NMDA receptor antagonist dextromethorphan (DMO) is able to
diminish the post-stimulation effects of both anodal and cathodal stimulation, and
a Na+ channel-blocking carbamazepine (CBZ) is able to abolish anodal effects,
indicating that the after-effects of anodal tDCS require a depolarization of
membrane potentials. Similar to the induction of established types of short or
long-term neuroplasticity, a combination of glutamatergic and membrane
 Transcranial Direct Current Stimulation and Neuroplasticity 69

mechanisms is necessary to induce the after-effects of tDCS. Nitsche et al. (2004)

also demonstrated that tDCS after-effects in human are abolished when NMDA
receptors are blocked, while facilitating NMDA receptor activity prolongs the
increase in excitability caused by anodal tDCS.
Recently, through animal study, Rohan et al (2015) investigated the potential
mechanisms of how in vivo tDCS can produce LTP-like plasticity. Their results
demonstrated that 30 minutes of brain stimulation in rats induced an enhancement
in hippocampal synaptic plasticity, as measured using extracellular recordings,
which were dose-dependent (effect of 0.25mA was greater than 0.10 mA) and
persisted at least for 24 hours after stimulation. In addition, a NMDA blocker
abolished this effect, suggesting the involvement of synaptic plasticity in after-
effects of tDCS. Based on these investigations, and considering that NMDA
receptors are able to function first in excitatory transmission and, secondly, in
modifying synaptic strength (D’Angelo and Rossi, 1998), the polarity-driven
changes of neuronal resting membrane potentials represent the fundamental
mechanisms of the long-lasting after-effects, culminating in changes of
spontaneous discharge rates and in NMDA receptor activation.
The contribution of GABA, Serotonin and Dopamine in LTP-induced by
tDCS also has been demonstrated. For example, excitatory (anodal) tDCS causes
locally reduced GABA while inhibitory (cathodal) tDCS causes reduced
glutamatergic neuronal activity with a reduction in GABA, probably due to the
close biochemical relationship between the two neurotransmitters (Stagg et al.,
2009). The reduction of GABAergic inhibition is believed to have a “gating
function” to increase (glutamatergic) plasticity (Ziemann et al., 1998). These
effects increase the probability of LTP occurring at those synapses that are
activated by behavioral processes such as motor training. Furthermore, the
blockade of serotonin reuptake increases LTP induced by anodal tDCS and
reverses cathodal LTD into LTP (Nitsche et al., 2009), whereas D2 antagonists
abolish cathodal and delay anodal tDCS-induced plasticity in healthy volunteers
(Nitsche et al., 2006), demonstrating the importance of dopamine and serotonin in
human tDCS. Interestingly, stimulation of the rat frontal cortex significantly
enhances extracellular striatal dopamine but only in the context of cathodal tDCS
(Tanaka et al., 2013).
Beside the involvement of Glutamatergic receptors in mechanisms underlying
LTP and LTD induced by tDCS, the contribution of neurotrophic factors, as brain
derived neurotrophic factor (BDNF), are important for changes at the synaptic
level that promote long term synaptic strengthening.
 Joanna Ripoll Rozisky et al., 2015

Figure 2. Mechanism of Long-term Potentiation induced by anodal tDCS.

Schematic illustrating the effects of anodal tDCS on the synapses of superficial neurons in the
target cortical area. Anodal stimulation depolarizes the neuronal membrane and glutamate is
released by pre-synaptic neuron and binds in NMDA and AMPA receptors. Despite the
depolarization, there is increase of intracellular Ca+2 in postsynaptic neuron, which can activate
protein kinases, such as Calcium/calmodulin-dependent kinase (CaMK). In turn, protein kinases
modulate numerous neuronal signaling pathways leading to the transcription, translation, and
insertion of new glutamate receptors (Pang et al., 2010). In a long-term mechanism, CaKM
activate CREB (transcription factor), which mediates gene transcription and formation of new
proteins.

Glutamate
 Transcranial Direct Current Stimulation and Neuroplasticity 71

Contribution of Brain-derived Neurotrophic Factor

Neurotrophins (NTs) or neurotrophic factors are known originally by

regulating the survival, growth and neuronal differentiation (Davies, 1994). They
are represented by a family of proteins comprises the following members: NGF,
BDNF, NT-3 (neurotrophin 3) and NT-4/5 (neurotrophin 4/5). All NTs bind with
low affinity to transmembrane receptors p75 and each one binds with high affinity
at one of tyrosine kinase receptor subtypes (trk): NGF binds in trkA, BDNF and
NT4 / 5 bind in trkB, and NT3 binds in trkC. Activation of the trk receptors by
their ligands leads to phosphorylation of its different residues and the activation of
different signaling pathways such as the MAPK pathways. In fact, besides their
classical role in supporting neuronal survival, NTFs are important mediators of
neuronal plasticity where they participate of all steps of neural plasticity process,
from axonal and dendritic growth to synapse formation and function (Lu et al.,
2005). In particular, the neurotrophin brain derived neurotrophic factor (BDNF)
has emerged as fundamental mediator of neuroplasticity. This neurotrophin is
abundantly found in brain regions particularly relevant for plasticity and shows an
activity-dependent regulation of expression and secretion (Bramham and
Messaoudi, 2005). The facilitation of BDNF on glutamatergic synaptic
transmission, via phosphorylation of NMDA receptor, is an important mechanism
for the central neuroplasticity, such as LTP (Schinder and Poo, 2000; Chao,
2003).
BDNF is demonstrated to modulate the neuroplasticity process induced by
tDCS in both humans and animals. Fritsch et al (2010) showed through animal
experiments that BDNF is pivotal molecule to induce LTP-dependent of tDCS.
They reported that BDNF secretion was enhanced after anodal tDCS coupled with
repetitive low-frequency synaptic activation (LFS) applied in mice induced LTP,
which does not occur in mutant mice (knockout for BDNF and trkB receptor).
Furthermore, anodal tDCS over the primary motor cortex (M1) in human induced
minor effects on individual with a reduced polymorphism BDNF expression
(Val/Met carriers) during a pinch-force task. In contrast, one session of anodal
tDCS does not induce change in BDNF plasma levels in healthy subjects (da Silva
et al., 2015). The authors reported that one tDCS session is not considered able to
induce changes in BDNF, i.e., it is necessary continuous tDCS sessions to induce
long-lasting changes in the levels of this neurotrophin. Also, recent animal studies
have demonstrated changes in BDNF levels in brain structures after repetitive
anodal stimulation. These results can suggest BDNF as a great biomarker of long-
lasting effects of tDCS (Spezia Adachi et al., 2015; Filho et al., 2015). Both
results highlight the importance of tDCS to induce neuroplasticity through BDNF
secretion and, consequently, improvement of motor skills and top-down
modulation in human and mice (Fritsch et al., 2010).
 Joanna Ripoll Rozisky et al., 2015

Assessment of Neuroplasticity induced by tDCS

Techniques for investigating the neuroplasticity in humans generally are

non-invasive and painless methods that use brain scans and brain blood flow
measure by functional Magnetic Resonance Imaging (fMRI), cortical blood flow
measure through near infrared spetrocscopy (NIRS), evaluation of cortical
excitability and motor function through TMS, and neuronal electrical activity
through electroencephalogram (EEG). These techniques associated with clinical
behavioral observations indicative of improved neurological function and
rehabilitation have been used and considered sufficiently to predict the long-
lasting effects induced by tDCS. Here, we will describe how fMRI, NIRS, TMS
and EEG techniques can demonstrate some of the indicative effects of
neuroplasticity.

Functional Magnetic Resonance Imaging (fMRI)

Functional magnetic resonance imaging uses magnetic resonance technology

that measures the brain blood flow–dependent response related to changes in
cortical activity and oxygen demand (Kimberley and Lewis, 2009; Huetel et al.,
2009). When an area of the brain is being activated, blood oxygen flow to that
region also increases in response to enhanced metabolism. Thus, fMRI is based on
the fact that neuronal activation is linked to hemodynamic changes. With this
technique is possible to characterize cortical and intracortical hemodynamic
changes and neuronal activation indicating enhanced or diminished intracortical
processing of a region (Heeger et al., 2002). Thus, fMRI provide important
information of brain connectivity changes, thus setting the stage for the
development of theories of neuroplasticity, specifically for functional
reorganization of neural networks and adaptation.
Several studies have used tDCS coupled to fMRI allowing identifying the
neural mechanisms underlying tDCS effects with high spatial resolution of
hemodynamic and neural activity through the entire brain. For example, Meinzeer
et al. (2012) observed that anodal tDCS increase the connectivity of structurally
and functionally connected language-related areas during task-performance
associated with improvement of cognitive memory. Stagg et al. (2011)
demonstrated, for the first time, that the anodal tDCS in the ipsilesional brain
hemisphere change significant behavioral improvements that are associated with a
functionally increase in activity within the ipsilesional primary motor cortex in
patients with a wide range of disabilities following stroke. The main advantage of
fMRI over other techniques is measure correlates of neuronal activity not only
under or in close proximity to the externally applied electrode, but also in remote
brain areas before, during and after stimulation. However, some of its limitations
 Transcranial Direct Current Stimulation and Neuroplasticity 73

are the requirement for participant immobility and high operational cost, which
have stimulated a need for lower-cost neuroimaging techniques, such as NIRS and
EEG, that are portable and can be used in freely moving participants performing
everyday tasks.

Near infrared Spectroscopy (NIRS)

NIRS is an optical technique based on the principle that light from the near
infrared (NIR) spectroscopy in the range 700 nm to 1000 nm can pass through the
skin, soft tissue and bone, with relative ease, and can penetrate into the brain
tissue to a depth of up to 5 cm in the adult brain and 8 cm in the brain of a
newborn (Bartocci, 2006; Wolfberg and Plessis, 2006). The light is mainly
absorbed by two chromophores: hemoglobin and cytochrome aa3. A chromophore
is a substance that absorbs light of a certain wavelength (e.g., NIR light spectrum
ranging from approximately 650 nm to 1000 nm), and chromophores found in
living tissues are HbO2, HbH, and cytochrome oxidase (Soul and Plessis, 1999).
Each of these chromophores has their peak absorption of NIR light at a different
and specific wavelength. The signal obtained with the NIRS is based on light
absorption by hemoglobin, which in turn depends on the oxygenation state of
hemoglobin flowing through the tissue. Thus, NIRS measures the relative change
in concentration of HbO2 and tissue intravascular HbH (Soul and Plessis, 1999;
Bartocci, 2006; Wolfberg and Plessis, 2006).
Studies with NIRS associated with tDCS have provided insights of
neuroplasticity related to stimulation. Merzagora et al. (2010) reported that fNIRS
captured the activation changes induced by the tDCS stimulation on the anterior
prefrontal cortex before and after stimulation. The anodal stimulation induced a
significant increase in oxyhemoglobin (HbO(2)) concentration, and this effect was
localized in time and lasted up to 8-10 min after the end of the stimulation. Khan
et al. (2013) compared the effects of bi-hemispheric tDCS on altered
hemodynamic patterns in the sensorimotor cortex and their relationship to muscle
activity and motor task performanc. Recently, Ishikuro et al. (2014) investigated
the association between frontal and sensorimotor cortices and motor learning
using NIRS system. Authors reported a significant increase of hemodynamic
responses and improvement in task performance with anodal tDCS of anterior
dorsomedial prefrontal cortex.

Transcranial Magnetic Stimulation (TMS)

Transcranial Magnetic Stimulation is a painless technique that uses a

magnetic field to induce an electrical current in specific nerve cells. Although
TMS has been used as a non-invasive brain stimulation technique for treating
neurological and psychiatric diseases, it is also widely applied to evaluate the
 Joanna Ripoll Rozisky et al., 2015

corticospinal tract circuitry, i.e, to assess the cortical connectivity projecting onto
the primary motor hand area (O’Shea et al., 2008). When a magnetic stimulus
through TMS is applied over the primary motor cortex, motor evoked potentials
(MEPs) can be recorded from contralateral extremity muscles. The amplitude of
the MEP reflects the integrity of the corticospinal tract and the excitability of
primary motor cortex and nerve roots. For example, patients with multiple
scleroses show abnormal MEPs, whilst the intact MEPs indicate normal
connectivity of corticalspinal tract (for review see Kobayashi and Pascual-Leone,
2003).
Concerning the investigation of after-effects of tDCS, TMS has been used
for exploring neuroplasticity through the evaluation of excitability of intracortical
circuits in the motor cortex. Recently Vaseghi et al (2015) explored the effects of
cathodal tDCS over primary motor (M1), sensorimotor (S1) and dorsal lateral
prefrontal (DLPFC) cortices excitability since these areas could be connected to
painful symptoms. Authors reported that after M1, S1 and DLPFC stimulation
there was a decrease of S1 and M1 excitability, which confirm the functional
connectivities between these cortical sites involved in pain processing. Thus,
TMS is a very useful tool that allows investigating brain excitability changes and
contributing to understand the mechanisms underlying the after-effects of tDCS.
Electroencephalogram (EEG)

As well as the above-described techniques, EEG also is non-invasive and

painless technique used to measure the brain activity generates neural electrical
signals that are graphically recorded through electrodes placed along to the scalp.
In clinical contexts, EEG refers to the brain's spontaneous electrical activity
recorded over a period of time (Niedermeyer and da Silva 2004). From the
electroencephalogram signals it can be analyzed four oscillatory different brain
waves, which will predicts the brain state: Beta (normal waking state), Alpha
(relaxed and asleep state), Theta (deep relaxation state), Delta (deep sleep state).
Studies have investigated the effects of tDCS on EEG. Lauro et al (2014)
reported that anodal stimulation modulated cortical excitability in both target and
contralateral hemispheres, indicating that tDCS can achieve regions far from
target cortical area. Cosmo et al (2015) demonstrated that anodal tDCS over left
dorsolateral prefrontal cortex improves functional brain connectivity in
individuals with attention-deficit/hyperactivity disorder. Their results also reveal
that although the effects of tDCS are selective, its modulatory activity spreads for
other regions of the brain.
The main advantages over other techniques are that EEG has superior
temporal resolution, reflecting timing of neuronal activity more accurately
compared to fMRI and greater spatial resolution compared with TMS-indexed
cortical excitability.
 Transcranial Direct Current Stimulation and Neuroplasticity 75

CONCLUSION

This chapter highlights the known mechanisms underlying the short-

effects (cortical and intracortical excitability) and long-lasting effects (LTP and
LTD) induced by tDCS. All these process, from neuronal depolarization through
anodal stimulation and hyperpolarization through cathodal, activation of NMDA
and GABA receptors, activation of signaling pathways, release of BDNF and a
number of neurotransmitters, formation of new synapses through dendritic spines
support the key role of tDCS in neuroplasticity. Thus, understanding all the
mechanisms of neuroplasticity-induced by anodal and cathodal tDCS and
studying the main potential factors of intervention that may influence
neuroplasticity can improve our practice in rehabilitation using this new tool and
promise non-invasive therapy.
 Joanna Ripoll Rozisky et al., 2015

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