Introduction to Transcranial Current Stimulation

Introduction
to Transcranial
Electrical
Stimulation
 2

Introduction to
Transcranial Electrical
Stimulation

Roser Sanchez-Todo
Biophysical modeling specialist

Giulio Ruffini
Neuroelectrics president
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1
Introduction 4
1.A A brief history of tES 4
1.B Basic definitions: tDCS, tACS, tRNS 5
1.C Other non-invasive brain stimulation (NIBS) techniques 7

2
Biophysics 8
2.A Introduction: the electric brain 8
2.B Electric fields 9

3
Neurophysiological mechanisms 9
3.A Basic mechanism model 9
3.B Neurophysiological effects of tES 11
3.C Neuroplasticity, LTP and LTD 13

4 Conclusions 14

5 References 16
 4

1 Introduction
1.A A brief history of tES
Transcranial electrical stimulation (tES, or tCS as it is also known) is a
noninvasive brain stimulation technique that passes electrical currents
through the brain in order to alter brain function. Its origins follow the history
of the discovery of electricity itself.

The first attempts of electric stimulation used electrosensitive animals

such as the torpedo fish and examined the effects of electrical discharge over
the scalp for headache pain reduction (Priori, 2003; Figure 1).

In 1780, Italian scientist Luigi Galvani discovered that the muscles of dead
frog legs contracted by the application of electricity – the first experimental
demonstration of bioelectrical stimulation. This in turn inspired Mary Shelley
to write Frankenstein.

Studies in the 19th and 20th centuries implemented the use of galvanic
currents in the treatment of psychiatric disorders. Electroconvulsive therapy
(ECT) emerged in the 1930s and the first patient to have been treated with
this therapy, in 1939, showed epileptogenic activity via the use of strong
electrical currents.

In parallel, work in the 20th century continued with research using low-
intensity currents with a recent resurgence in the investigation of weak direct
and alternating currents (Nitsche & Paulus, 2000). In this study, researchers
demonstrated that by applying a direct current through the scalp, the
excitability of brain tissue changes up to 40%, which was similar to findings
that utilize transcranial magnetic stimulation. (TMS, see section 1/C).

Figure 1. a) Torpedo fish (Electric Ray, from Wikipedia) b) Rendering

of the treatment using torpedo fish (Perdikis P., 1977)
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1.B Basic definitions: tDCS, tACS, tRNS

What does tDCS stand for?

tES comprises a number of different techniques: transcranial direct

current stimulation (tDCS), alternating current stimulation (tACS) and
random noise stimulation (tRNS). More general forms are possible (i.e., with
different temporal waveforms), but the common characteristics include
weak currents (typically below 2 mA) and a spectrum (frequency range)
below 100 Hz (relatively low frequencies). See Table 1 for a summary of
these different tES techniques.

What is the difference between TMS and tES?

tES is similar to transcranial magnetic stimulation (TMS), as both work by

inducing electric fields in the brain (see below). However, TMS creates very strong
electric fields that make neurons fire through the induction of very short electric
field pulses.

On the other hand, tES induces weak electric fields that gently modify
neuronal oscillations and is typically applied during relatively long periods (20
minutes or more).

Multielectrode, high-definition tES can be used to produce controlled, precise

electric fields in the brain.
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tDCS tACS tRNS

Waveform
Stimulation

Current delivered Direct current delivered at Alternating current, in Alternate current along
low intensities, from 0.5 to sinusoidal waves. Average with random amplitude and
2 mA intensity, 0.25-1mA; frequency. Average intensity,
frequency 1,10,15, 30 and -500 to 500µA with providing a
45; voltage, 5-15mV current of 1mA; frequency
from 0.1 to 640 Hz)

Typical time 20 min 2-5 min 10 min

for stimulation

Side effects Tingling, itching, redness Tingling, itching, redness Tingling, itching

EEG Increased slow oscillatory IIncreased alpha (8-12Hz) No change

activity (3Hz) and high theta (3-8Hz)
activity (Antal, Boros et al.,
2008)

Cortical Increased excitability with No change Apparently enhances

excitability anodal stimulation (Boros, (Antal, Boros et al., 2008) corticospinal excitability
Poreisz, Munchau, Paulus (Terney et al., 2008); although
& Nitsche, 2008; Nitsche et other studies do not support
al., 2003) and decreased this finding (Fertonani et al.,
excitability with cathodal 2011), Snowball et al. (2013)
stimulation (Ardolino, Bossi, suggest modulation of cortical
Barbieri, & Priori et al., 2005) excitability with reduction of
regional cerebral blood flow
without affecting regional
cerebral metabolic rate of
oxygen consumption.

Neurotransmitters Increased brain-derived No known changes Possibly activation of

neurotropic factor (BDNF) glutamate mediated
(Fritsch et al., 2010) and synapses (Terney et al., 2008)
extrasynaptic GABA (Stagg et
al., 2011) and decreased
interaction of glutamate with
its receptor (Fritsch et al.,
2010)

Table 1 Summary of the different forms of tES stimulation. * Note that the current is delivered
through one or more active electrodes (anode) and returned via other electrodes (cathodesCurrent
must be conserved: what goes in must come out.
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1.C Other non-invasive brain stimulation (NIBS) techniques

Apart from tES, another widely used non-invasive brain stimulation (NIBS)
technique is transcranial magnetic stimulation (TMS).

TMS is based on the application of strong, short (pulsed), localized

electric fields to the cortex, and, unlike tES, is capable of inducing action
potentials (Wassermann et al., 2008).

The effect of the membrane potential (polarity-dependent) is the same for

TMS and tES, except for the magnitude: tES has a magnitude of 0.1-0.4 V/m
and TMS can be higher than 100 V/m. However, the relative importance of the
effect of the different parts of the cell may not be the same (i.e. soma and
apical dendrites, see Section 3.A). This is because TMS is suprathreshold (it
generates action potentials, traveling waves along a neuron where the
membrane potential rapidly rises and returns to baseline) while tES is not.

In TMS, what matters is where the suprathreshold depolarization takes

place, since that is where the action potential will be generated. In tES,
subthreshold polarization effects occur at the soma and along neuronal fibers.

Regarding focality, one can argue that bipolar tES is not as focal as TMS
(see Figure 2), but that is without consideration of multichannel tDCS
montages or other tES types. While the amplitude of the current in tES
remains subthreshold and lower than TMS (it would be too painful to increase it),
a multichannel montage can achieve similar focality to TMS.

Other suprathreshold NIBS include transcranial electrical stimulation (tES)

and electroconvulsive therapy (ECT), both of which involve much stronger
currents and electric fields in the brain.

Figure 2. Models of electric fieldS of the cortex in assessing amplitude and focality of the
stimulation. a) bipolar tES, b) multichannel tES and c) TMS. This figure is from Miranda et al. 2016
(private communication).
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2 Biophysics
2.A Introduction: the electric brain
The brain is a complex web and incredible information processing machine
that uses electrical signals to transport information, encode memories, control
our bodies, process sensory inputs, make decisions, reason and much more.

If the brain is a network, the node and workhorse of the brain is the neuron.
Neurons receive signals from other connected neurons in the brain’s network
through synapses, add them up, and output their own signals for other neurons
to process (Figure 3).

An important finding stemming back (at least) to the work of Galvani in

1730 is that our nervous system relies on electricity to process signals.
Information within a neuron is carried by electrical signals, although from
neuron to neuron the signals travel mostly from chemicals and
neurotransmitters.

Thus, our brains can be seen as electrochemical information processing

systems, much like computers, but —for now at least— vastly more complicated.

As often quoted, the human brain has 100 billion neurons, and each neuron
connects to many others (as many as 10,000), resulting in about 100 trillion
connections. Try to imagine such a network - it is mind-boggling.

The key players in this story are the action potential and the membrane
potential. The action potential is the change in electrical potential associated
with the passage of an impulse along the membrane of a nerve cell. The
membrane potential is sensitive to its electrical environment (membrane
polarization, as it is known) and determines if and how signals propagate
through the neuron. But, in order to describe this further, we need a key concept:
the electric field.

Figure 3. a) Picture of a pyramidal neuron (the original uploader was Nrets at Wikimedia). b)
Simplification of the connections in the brain regulated by electrical signals.
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2.B Electric fields
Physicists describe electrical phenomena using a specific mathematical
concept: the electric field.

To understand what a field is, think of a poppy field (or a cornfield if you
prefer). At each location in the field, we allocate a number, or even better, a
little arrow with a given length and direction. And that is, in essence, a vector
field: the specification of a vector at each point in space. The electric field
vector at a given location tells charges there how to move by specifying a
force on them. If you want to predict the future of a charge in space, you need
to have a map of the electric field.

In order to understand how brain stimulation works, we need this concept

because brain stimulation essentially creates electric fields in the brain.

When we apply transcranial current stimulation using scalp electrodes, we

actually induce an electric field in the cortex (among other places) that
affects the way charges move and how neurons there will operate. This is the
key to understanding the basic mechanism behind transcranial current
stimulation. And here we must return to the neuron membrane.

Figure 4. Representation of electric fields. a) Poppy field, a metaphor of an electric field when the
wind blows. b) 3D vector field. c) Realistic representation of an electric field (black arrows) on a
realistic model of the brain.

3 Neurophysiological mechanisms
3.A Basic mechanism model
If the way neurons process information depends on the electrical state of
the neuron membrane, what is the effect of a weak electric field such as the
one generated by tES (one that cannot trigger a neuron to fire, unlike TMS)?

In essence, a weak electric field will shift the membrane operating point in a
way that will make the neuron more or less excitable, or more or less likely to
fire given some input. This means that an electric field will immediately alter the
way parts of the brain processes information.
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Thus, the effects of tES during stimulation are derived from the alteration of
neuronal membrane potentials. The membrane potential shift at time t can
change the probability of an action potential (or firing of an impulse) at that time.

If the effect is constant (tDCS, where the current and electric field are
constant), this translates into a shift of the firing rate of the neuron. The shift
will be positive or negative depending on the direction of the electric field
relative to the neuron, as described above.

If the shift is time dependent, as in the case of tACS, there will be shifts in
firing rates that will covary with the stimulating electric field, and will average to
zero. In this case, this pertains to spike timing changes.

The shift of the membrane potential is the fundamental mechanism behind

tES, and there are many research experiments studying and quantifying it
(Ruffini et al., 2013). The effect is especially strong with an elongated, orderly
type of neuron called pyramidal cells (see Figure 3a) and depends on the relative
orientation of the electric field vector (i.e., where it is pointing) and the
orientation of pyramidal cells (see Figure 5).

Figure 5. Basic interaction of electric fields with elongated neurons like pyramidal cells. a) Electric
field (dashed lines) through the scalp representation. b) Vectors in the direction of the neuron
(lambda) and the electric field. c) Excitatory electric field (anodal), depolarization of the pyramidal
neurons. d) Inhibitory electric field (cathodal), hyperpolarization of the pyramidal neurons.

But there is a second, crucial part that is needed: the brain has memory.
The operating changes induced by the electric field will leave an imprint on
the brain’s web, altering the way some neurons wire to each other. This is
called neuroplasticity.
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Neuroplasticity: A simple rule of thumb is that “neurons that fire together,

wire together” (Figure 7). If a neuron A participates contributes to the firing of
a connected neuron B repeatedly and consistently, then the connection
between the two will be reinforced. This is called Hebb’s rule, and its outcome
is Hebbian learning.

By shifting the operating point of neurons, tES can affect the way parts of
the brain participate in learning tasks, and thus contribute to its neuroplasticity
and rewiring.

3.B Neurophysiological effects of tES

The use of transcranial stimulation produces a flow of current through the
scalp, skull, cerebrospinal fluid (CSF) and brain tissue. Although a good
portion of the current is shunted through the scalp and CSF (the precise
amount depends on the montage used), part of the current penetrates into
the brain producing an electric field of 0.1-0.4 V/m per mA of current applied.

The relationship between current density J (in amperes per square meter)
and electric field E (volts per meter) is simple: J = σ E, where σ is a constant
called conductivity. Both J and E are vectors, parallel to each other.

The persistent and weak electric field produced by tDCS modifies the
membrane potential, influencing the level of excitability after synaptic input
(Rahman et al., 2013, Ruffini et al., 2013), which, in turn, modulates the firing rate
of individual neurons (Miranda et al., 2006; Wagner et al., 2007).

Since tDCS induces a subthreshold current, it does not induce action

potentials (Bikson et al., 2004).

The electric field produced by tDCS modulates the endogenous

spontaneous activity in a polarity-dependent fashion (Figure 5):

Anodal stimulation (Figure 6a) produces a current and electric field pointing
inwards to the cortex, which will depolarize the soma of the pyramidal neurons
they since are oriented parallel to the surface, and hyperpolarize the apical
dendrites.

Cathodal stimulation (Figure 6b) produces a current and electric field that
points outward from the cortex, which will hyperpolarize the soma of the
pyramidal neuron, and depolarize the apical dendrites (Radman et al., 2009;
Zaghi et al., 2010).
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Figure 6. a) Anodal stimulation in a bipolar montage where 1mA of current is injected through
electrode T8 and returns in Cz. b) Cathodal stimulation with the same parameters but inverted sign in
electrode T7. Positive numbers indicate electric field or current density vectors pointing into the
cortex, negative numbers pointing out.

As discussed earlier, the clinically relevant effects of tES have to do with

plastic changes in excitability and connectivity of the brain. For example,
Nitsche and Paulus demonstrated in their 2000 paper that the application of
tDCS during several minutes induced a change in excitability of the cortex
(as probed by TMS) as well as more than one hour after tDCS. It is believed
that repeated application of tDCS can induce long lasting changes in brain
connectivity. tDCS effects can be modified, abolished, prolonged or even
reversed by co-application of drugs acting on the central nervous system
and interfering with plastic mechanisms. tACS induces a time varying shift
of the membrane potential. tACS delivers time-varying sinusoidal current to
the brain. For a review of cellular mechanisms of tACS, see Reato et al.,
2013. tRNS also induces a time varying shift of the membrane potential.
However, the electric field temporal waveform is noise. This has the effect
of a random perturbation of the membrane potential.

This dynamic shift will coexist with endogenous ones, affecting the timing
of spikes. Depending on their relative timing, endogenous (i.e., those self-
generated in the brain) and exogenous membrane shifts will sum or cancel. In
the latter case, we talk of entrainment (reinforcement of ongoing
oscillations, Frohlich & Mccormick, 2010; Reato, Rahman, Bikson, & Parra
2010) or resonance phenomena (Ali, Sellers, & Frohlich 2013; Antal & Paulus,
2013). The particular frequency chosen for tACS is selective for
interactions with endogenous oscillations at the same frequency and their
role in cognitive functions, for example. The effect can be utilized for
rehabilitative or cognitive enhancement interventions in humans
(Santarnecchi et al. 2015).
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Electroencephalographic (EEG) changes during tACS at low-intensity

have been found: Zaehle, Rach, and Herrmann (2010) performed a study
investigating tACS over the occipital cortex while measuring alpha activity
from EEG. They found that tACS increased alpha activity, which could
potentially be useful for treating patients with cognitive dysfunction due
to the modulatory effects of tACS seen in this and previous studies.

The effects observed in EEG recordings provide initial mechanistic data

to explain tACS results, presenting additional evidence for the frequency
and intensity-specific effect of this technique; however, further studies are
needed to clarify the cellular mechanisms of this intervention.

Dynamic system theory suggests that noise can amplify the signal to
noise ratio of a non-linear system (this is called stochastic resonance). That
is, a weak, sub-threshold signal (e.g., a sinusoidal signal) can be more easily
detected if noise is added. tRNS effects are excitatory and from the point of
view of stochastic resonance, will amplify signals associated to the
performance of a task, which can be reinforced. Neuroplastic effects will
then support learning of the task. tRNS has been shown to further promote
cognitive training and transfer effects in healthy adults without harmful
effects (Looi et al., 2017).

3.C Neuroplasticity, LTP and LTD

Neuroplasticity in the brain is typically described by Hebbian learning
(Figure 7). The Canadian psychologist Hebb proposed (1949) that memories
are formed by the strengthening of synaptic connections (Costandi, 2016).

Hebb wrote,

“Let us assume that the persistence or repetition of a reverberatory activity

(or “trace”) tends to induce lasting cellular changes that add to its stability. ...
When an axon of cell A is near enough to excite a cell B and repeatedly or
persistently takes part in firing it, some growth process or metabolic change
takes place in one or both cells such that A’s effciency, as one of the cells firing
B, is increased”.

In other words, neurons that fire together, wire together. And, vice versa,
neurons that “fire apart”, wire apart.

By making neuron A fire repeatedly and causing neuron B to fire as well,

the synaptic connection between them is made stronger, making the synapse
more effective in altering the membrane potential of the downstream neuron.
This is called Long Term Potentiation (LTP). A receptor in the post-synaptic
neuron membrane is involved in this process: the NMDA receptor.

The counterpart to LTP is long-term depression, or LTD. Whether LTP and

LTD occur is a matter of timing (spike timing dependent plasticity). If the
downstream neuron fires shortly after (< 20 ms) the upstream one, LTP occurs.
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If it happens before or long after, LTD occurs. This is the precise expression of
“fire together” or “fire apart”. By shifting membrane potential and altering
network dynamics (firing rates, spike timing), tES interferes with natural
plasticity mechanisms, ultimately altering the way neuronal circuits rewire.

Figure 7. If the presynaptic neuron repeatedly or persistently participates in causing the postsynaptic
neuron to fire (presynaptic neuron 1), their connection will be strengthened. And vice-versa, if the firing
of these two neurons is not causally related, they will disconnect (presynaptic neuron 2).

4 Conclusions
Interest in neuromodulatory interventions has increased in recent
decades, as it is considered a promising tool for the management of
numerous conditions that range from psychiatric diseases to chronic pain.
From this, several researchers and clinicians have turned to transcranial direct
current stimulation tDCS devices for their study and practice.

tDCS trials, or non-invasive brain stimulation with weak electrical currents,

have shown potential benefits by the induction of changes in cortical
excitability and, consequently, neuroplastic effects.

The effects amplified by these techniques depend on the parameters of

the stimulation, including intensity, duration, and frequency, which explains
the variability of the results.

While there is increased understanding of the mechanisms of tDCS, the

mechanisms that underline other methods described here are less
understood. Therefore, more research is needed, which will lead to a better
understanding of the neurophysiological effects and mechanisms of
transcranial current stimulation, and the suitability of each method to
enhance the human brain.
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“Neurons
that fire together,
wire together”
Donald Hebb

“The unappreciated
peril: If tES
can change one
function, it can change
another”
from The Stimulated Brain,
Roi Cohen Kadosh, 2014
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5 References
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