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Immediate neurophysiological effects of transcranial electrical stimulation

December 2018
Nature Communications 9(1)

DOI:10.1038/s41467-018-07233-7

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CC BY 4.0

Authors:

Anli Liu

NYU Langone Medical Center

Mihály Vöröslakos

New York University

Greg Kronberg

Icahn School of Medicine at Mount Sinai

Simon Henin

NYU Langone Medical Center

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Noninvasive brain stimulation techniques are used in experimental and clinical fields for their potential effects on brain network dynamics and behavior. Transcranial electrical stimulation (TES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), has gained popularity because of its convenience and potential as a chronic therapy. However, a mechanistic understanding of TES has lagged behind its widespread adoption. Here, we review data and modelling on the immediate neurophysiological effects of TES in vitro as well as in vivo in both humans and other animals. While it remains unclear how typical TES protocols affect neural activity, we propose that validated models of current flow should inform study design and artifacts should be carefully excluded during signal recording and analysis. Potential indirect effects of TES (e.g., peripheral stimulation) should be investigated in more detail and further explored in experimental designs. We also consider how novel technologies may stimulate the next generation of TES experiments and devices, thus enhancing validity, specificity, and reproducibility.

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REVIEW ARTICLE

Immediate neurophysiological effects

of transcranial electrical stimulation

Anli Liu 1,2, Mihály Vöröslakos3,4, Greg Kronberg5, Simon Henin 1,2,

Matthew R. Krause 6, Yu Huang5, Alexander Opitz7, Ashesh Mehta8,9,

Christopher C. Pack6, Bart Krekelberg10, Antal Berényi 3, Lucas C. Parra 5,

Lucia Melloni1,2,11, Orrin Devinsky1,2 & György Buzsáki 4

Noninvasive brain stimulation techniques are used in experimental and clinical ﬁelds for their

potential effects on brain network dynamics and behavior. Transcranial electrical stimulation

(TES), including transcranial direct current stimulation (tDCS) and transcranial alternating

current stimulation (tACS), has gained popularity because of its convenience and potential as

a chronic therapy. However, a mechanistic understanding of TES has lagged behind its

widespread adoption. Here, we review data and modelling on the immediate neurophysio-

logical effects of TES in vitro as well as in vivo in both humans and other animals. While it

remains unclear how typical TES protocols affect neural activity, we propose that validated

models of current ﬂow should inform study design and artifacts should be carefully excluded

during signal recording and analysis. Potential indirect effects of TES (e.g., peripheral sti-

mulation) should be investigated in more detail and further explored in experimental designs.

We also consider how novel technologies may stimulate the next generation of TES

experiments and devices, thus enhancing validity, speciﬁcity, and reproducibility.

Electrical stimulation to the brain has a long history in both science and medicine. In 1867,

Helmholtz discussed how electrical currents applied to the head can generate visual sen-

sations1. Currents as low as 0.3 mA could induce phosphenes, and stronger currents could

induce brighter and more lasting visual effects2. Subsequent studies conﬁrmed that these visual

phenomena result from retinal rather than direct brain stimulation3,4.

Early noninvasive electrical stimulation technologies used high intensities to directly affect

brain activity (see Box 1). Electroconvulsive therapy, introduced into psychiatry in the 1930s,

used currents of up to 60 mA to induce generalized seizures5. Subsequent studies on

DOI: 10.1038/s41467-018-07233-7 OPEN

1New York University Comprehensive Epilepsy Center, 223 34th Street, New York, NY 10016, USA. 2Department of Neurology, NYU Langone Health, 222

East 41st Street, 14th Floor, New York, NY 10016, USA. 3MTA-SZTE ‘Momentum’Oscillatory Neuronal Networks Research Group, Department of

Physiology, Faculty of Medicine, University of Szeged, 10 Dom sq., Szeged H-6720, Hungary. 4New York University Neuroscience Institute, 435 East 30th

Street, New York, NY 10016, USA. 5Department of Biomedical Engineering, City College of New York, 160 Convent Ave, New York, NY 10031, USA.

6Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada. 7Department of Biomedical Engineering of Minnesota, 312 Church

St. SE, Minneapolis, MN 55455, USA. 8Department of Neurosurgery, Hofstra Northwell School of Medicine, 611 Northern Blvd, Great Neck, NY 11021, USA.

9Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, 350 Community Drive, Manhasset, NY 11030, USA. 10 Center for Molecular

and Behavioral Neuroscience, Rutgers University, 197 University Avenue, Newark, NJ 07102, USA. 11 Max Planck Institute for Empirical Aesthetics,

Grüneburgweg 14, 60322 Frankfurt am Main, Germany. Correspondence and requests for materials should be addressed to A.L. (email: anli.liu@nyumc.org)

or to G.Bák. (email: gyorgy.buzsaki@nyumc.org)

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1234567890():,;

electroanesthesia and electrosleep used subconvulsive current

intensities, delivered through large copper or platinum disks

covered with saline-soaked gauze over frontal and occipital scalp,

to affect large neocortical regions. To induce anesthesia, up

to 40 mA direct currents (DC) or alternating currents (AC; 1

Hz–200 Hz) were used (See Box 1), while weaker intensities

(3–10 mA) were typically needed for sleep induction6. More than

500 human surgeries were carried out under electrical anesthesia

supplemented with medication7, but serious side effects led to the

decline of the technique.

The remaining present-day application of high-intensity tran-

scranial electrical stimulation (TES, see Box 1) is for intra-

operative neuromonitoring. This technique, introduced by Mer-

ton and Merton (1980), uses high-intensity stimulation (up to

2000 V) through a pair of electrodes positioned over primary

motor cortex to generate a visible twitch in the contralateral hand

to monitor the functional integrity of central motor pathways

during resective surgery8–10. These early applications for high-

intensity TES6,11,12 laid the groundwork for subsequent experi-

ments which suggested that weak currents applied to the scalp

can also induce behavioral effects but without side effects and

without conscious awareness of the stimulation13,14. Compared to

other noninvasive neuromodulatory techniques such as tran-

scranial magnetic stimulation (TMS) and ultrasound stimula-

tion15, advantages of TES include low cost, portability, and

potential in-home applications, fueling a proliferation of human

trials16,17. However, a disadvantage of TES is that it may activate

excitable peripheral elements between the scalp electrodes,

including trigeminal nerve branches, the greater occipital nerve,

retina, and vestibular organs.

Despite more than 4000 publications (PubMed) on TES in the

past decade, we lack a mechanistic understanding of the

mechanism (or mechanisms) by which this technique produces

beneﬁcial or deleterious effects. Most TES studies place an elec-

trode above a targeted cortical region with the assumption that

the underlying neuronal activity will be boosted or suppressed.

While experiments in intact animals and computational models

have studied physiological and behavioral effects of TES, the

mechanisms are incompletely understood and their translation to

humans even more uncertain. It is also unclear whether TES

works through direct or indirect effects (see Box 1). This

mechanistic uncertainty explains why behavioral effects in

humans are often weak, variable and difﬁcult to replicate18,19.

In this Review, we discuss the immediate (i.e., acute, con-

current, or online, see Box 1) neurophysiological effects of elec-

trical ﬁeld stimulation in brain slices, rodents, non-human

primates, and humans. We compare experimental ﬁndings with

computational models, highlight the gaps in understanding, and

discuss novel methods to deliver spatially precise stimulation at

higher intensities than conventionally used, while reducing

unwanted peripheral effects. We close with recommendations for

future clinical and translational TES investigations. We do not

discuss here potential ofﬂine effects of TES, i.e. those effects

which occur or persist after the current has been switched off (see

Box 1). These have been reviewed elsewhere20,21.

Biophysics of induced electric ﬁelds

At each point within the brain, a scalar electric potential can be

measured relative to an arbitrary reference and expressed in Volts

(V). The electric ﬁeld

Eis the local change (gradient) of the

voltage;

Eis a vector whose amplitude is measured in Volts per

meter (V/m). All transmembrane currents from nearby neuronal

processes contribute to generate E

!22.

When a current is applied to brain tissue (as in TES), it affects

the polarization of cellular membranes, which in turn can alter

neuronal excitability. Terzuolo and Bullock23 ﬁrst demonstrated

this using DC stimulation applied with metal bars to the crayﬁsh

abdominal receptor and lobster cardiac ganglion neurons.

Induced electric ﬁelds as low as 1 V/m affected the timing of

action potentials while much higher ﬁelds triggered action

potentials in silent neurons23. However, the orientation of the

ﬁeld was also important: rotating the applied electric ﬁeld’s

orientation relative to the main neuron’s soma-dendritic axis

(e.g., from parallel to perpendicular to the main neuronal axis)

affected the strength and direction of the effects. These ﬁndings

Box 1 Terminology

Transcranial electrical stimulation (TES)—The technique of applying an electric ﬁeld at the scalp surface with the purpose of directly affecting brain

activity. Early efforts applied ﬁelds at high intensities for electroconvulsive therapy (ECT, 60 mA), electroanesthesia (40 mA), and electrosleep (3–10 mA).

More recent efforts have applied TES at lower intensities (typically 1-2 mA) to reduce peripheral side effects, such as skin sensation and phosphenes.

Direct current stimulation—Electrical current applied in a constant, unidirectional manner ﬂowing from anode to cathode. When DC stimulation is

applied across the scalp, it is commonly referred to as transcranial direct current stimulation (TDCS).

Alternating current stimulation—Electrical current applied in a varying, typically sinusoidal, waveform, with current ﬂowing from anode to cathode in

one half-cycle and in the reverse direction in the second half-cycle. When the AC stimulation is applied across the scalp, it is commonly referred to as

transcranial alternating current stimulation (TACS).

Electric ﬁeld—The difference in voltage between two locations (in the brain). The electric ﬁeld is a vector with both magnitude and direction, and is

measured in units of Volts/meter (V/m).

Direct effects—Potential effects of TES on the excitability of neurons in the brain, which include both immediate and cumulative effects.

Indirect effects—Potential side effects of TES on non-neuronal elements, including placebo, peripheral nerves, retina, cochlea, glia, immune system, and

blood ﬂow as well as cumulative, long-term metabolic effects on neurons.

Immediate effects—Potential effects of TES which occur simultaneously or acutely during stimulation. These effects are measured by changes in

neuronal ﬁring patterns or the local ﬁeld potential (deﬁned below). We use the terms acute, concurrent, or online as synonyms of the term “immediate.”

Ofﬂine effects—Potential effects of TES which may outlast the period of stimulation.

Local ﬁeld potential—a composite measure of electric current generated from all active cellular processes within a volume of brain tissue superimpose

at a given location in the extracellular medium and generate an extracellular potential V

(a scalar measured in Volts) with respect to a reference

potential. The difference in V

between two locations gives rise to an electric ﬁeld (a vector, V/m). The local ﬁeld is monitored by small intracranial

electrodes as opposed to those obtained by scalp EEG recordings.

Oscillations—Rhythmic ﬂuctuations in the local ﬁeld potential, which can range in frequency from ultraslow (0.05 Hz) to ultrafast (500 Hz), with

speciﬁc oscillation frequencies characterizing particular brain states.

Shunting—During TES application, the ﬂow of current away from the brain due to passage along a low-resistance pathway (skin, subcutaneous tissue),

and away from a high resistance pathway (the skull). Current shunting explains why only a small part of the current delivered through TES electrodes

actually reaches the brain surface.

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generalize to the mammalian brain. An anode on the pial surface

(cathode at depth) depolarizes neurons and increases neuronal

ﬁring frequency, while the reversed current ﬂow (surface cathode,

depth anode) hyperpolarizes neurons and reduces their ﬁring

rates24,25.

Yet, the above picture is an oversimpliﬁcation. First, it assumes

that the soma is singularly affected, but axon initial segment,

dendrites, and axon are also affected with different, unknown

sensitivities to electric ﬁelds. These combined and variable effects

on neuronal compartments can alter neuronal spiking19.In

addition, tonic depolarization of axon terminals could release

neurotransmitters in an axon branch-speciﬁc manner without

generating action potentials. Second, although ﬁelds perpendi-

cular to the soma-dendritic axis may have little inﬂuence on the

apical dendrites of pyramidal neurons26–28, they can activate

basal dendrites and dense local axonal arbors of basket and

chandelier interneurons. In addition, neurons with star-shaped

dendrites—many inhibitory interneurons, layer 4 stellate cells,

thalamocortical cells, and basal ganglia neurons—might be

affected equally by all ﬁeld orientations. These complexities

(Fig. 1) are relevant because the orientation of TES-induced

intracranial ﬁelds relative to these different neuronal populations

and compartments varies considerably29. In summary, the

inﬂuence of TES current depends not only on the amplitude but

upon how the induced electric ﬁeld relates to the three-

dimensional organization of neuronal compartments28,30,31.

Biophysical experiments and detailed computational models are

needed to fully understand these complexities.

Hypothesized immediate effects of electric ﬁelds on neural

activity

We deﬁne immediate effects of TES as those that occur simul-

taneously or acutely from the modulation of the membrane

potential by the external ﬁeld. For a sufﬁciently strong electric

ﬁeld, neuronal ﬁring rates should result from changes in a neu-

ron’s input/output function19, facilitated neurotransmitter release

from presynaptic terminals32, or ectopically induced spikes33.

With AC stimulation, current ﬂows from anode to cathode in

one half-cycle and reverses direction during the other half-cycle.

These half-cycles ﬁelds are equal magnitude but opposite direction.

Thus, during low-frequency AC stimulation, somata may be

alternately depolarized and hyperpolarized, which could mimic

effects of anodal and cathodal DC stimulation. If the applied AC

frequency is much faster than the neuronal membrane time

constant (~30 ms, or > 33.3 Hz), the fast-changing polarities of the

stimulation may reduce neuronal polarization34,35, and thereby

reduce unwanted peripheral nerve stimulation effects (see below).

In tACS studies, applied TES current is posited to affect the

brain’s native oscillatory patterns36–38 and thereby target cogni-

tive and therapeutic applications. While the magnitude of TES-

induced physiological effects varies with the strength of the

induced ﬁeld, the ‘effectiveness’of the stimulation and its con-

sequences on neuronal and network activity depend on many

other experimental variables and the brain’s state. We distinguish

ﬁve neural mechanisms that could affect network activity: sto-

chastic resonance, rhythm resonance, temporal biasing of neu-

ronal spikes, entrainment of network patterns, and imposed

patterns (Fig. 2). These ﬁve mechanisms of ﬁeld-induced effects

can cooperate or compete with each other and with endogenous

brain activity, and can occur simultaneously in different networks

of the same brain.

(1) Stochastic resonance. Because physiological (EPSP, IPSP)

and exogenous (TES) polarizing mechanisms are added, there is

no theoretical ‘minimum effective threshold’of the induced

electric ﬁeld39,40. When a neuron nears the threshold of spike

generation, a very small amount of applied ﬁeld can bias spike

timing or spike probability. This is known as ‘stochastic reso-

nance’41. Weak stochastic effects are hard to quantify in normal

networks with ﬂuctuating activity levels because the affected

neurons may be scattered in distant networks. Upon repeated

application of the ﬁeld, different neurons may be excited or

hyperpolarized, and thus it may be difﬁcult to generate repro-

ducible effects based on this mechanism alone. (2) Rhythm

resonance. Under well-controlled, closed-loop conditions, a very

weak ﬁeld can be precisely timed to the depolarizing phase of an

oscillating neuron’s membrane potential (see below). Even

without a closed-loop system, rhythm resonance may occur when

an AC ﬁeld is applied to a regular endogenous rhythm at

the same frequency, because the external ﬁeld can affect the

native oscillation at a similar phase during each cycle42–50. Such

phase matching may explain tACS beta oscillation phase-

dependent modulation of TMS-induced motor responses in the

motor cortex51. (3) Temporal biasing of spikes. Strong rhythmic

applied ﬁelds may reliably affect the membrane potential and,

consequently, spike timing of subsets of neurons. This mechan-

ism is related to stochastic resonance since the coincidence of

intrinsic and extrinsic polarization forces work together but the

same neurons are more reliably activated from trial to trial. Such

phase-locked temporal biasing of neuronal spikes by the rhythmic

+ + + + + + + + + + + + + + + + +

– – – – – – – – – – – – – – – – –

Fig. 1 The impact of orientation of neuronal compartments on TES-induced

excitability. Four idealized neurons are shown with different orientation

relative to the induced electric ﬁeld. The electric ﬁeld can affect the soma,

dendrites, axon initial segment and the axon tree differently. The

relationship between the electric ﬁeld vector and the morphology/

orientation of neurons and individual neuronal compartments determine

whether the neuron will be net depolarized or hyperpolarized

Field intensity (V/m)

Mechanisms

Stochastic

resonance

Rhythm

resonance

Temporal bias

of spikes

Network

entrainment

Imposed

pattern

Fig. 2 Five postulated mechanisms to affect online spiking of neurons and

networks patterns in response to different estimated magnitudes of TES.

While the ﬁgure illustrates distinct effects, in reality the boundaries of

mechanisms are blurred under most experimental conditions. Several

mechanisms can act simultaneously in different networks of the same

brain. The numbers on the vertical axis are merely estimates based on

current data and theoretical considerations

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NATURE COMMUNICATIONS | (2018) 9:5092 | DOI: 10.1038/s41467-018-07233-7 | www.nature.com/naturecommunications 3

forced ﬁeld may occur without affecting the overall ﬁring rates of

neurons. (4) Network entrainment. To entrain network patterns

of less regularity (e.g., slow oscillations of sleep) requires stronger

currents since exogenous patterns compete with native brain

rhythms19,40,45. (5) Imposed Pattern. Imposing an arbitrary

pattern on a neuronal network (e.g., enforcing theta activity on a

network with an endogenous beta rhythm) requires the strongest

ﬁeld to overcome the endogenous control of network neurons

(Fig. 2).

Spike and local ﬁeld potential (LFP) measurements are often-

used methods of measuring neural activity in vivo, each with

advantages and disadvantages. Spike measures are the most direct

read-out of TES effect on neural activity35, but are not always

available in animals and are rarely possible in humans. LFP is the

extracellular measure of transmembrane electric current gener-

ated synchronously by a nearby population of neurons, brought

about primarily by postsynaptic potentials52,53 (see Box 1).

Importantly, LFP measurements allow comparison between

human and animal experiments. The acute effects of tACS could

be measured by changes in the LFP amplitude, such as epilepti-

form spike-and-waves or the dominant alpha rhythm as a func-

tion of the tACS phase35,54. A related method is to measure

entrainment of slower rhythms by tACS (e.g., sleep slow oscilla-

tions, see Box 1), also measured by the amplitude of faster, cross-

frequency coupled patterns (e.g., sleep spindles)17,25 Quantifying

entrainment of rhythms at the same frequency of the applied TES

is difﬁcult with current methods due to the difﬁculty of separating

the artifact from the entrained physiological pattern, as discussed

in more detail below.

Acute effects of electric ﬁelds in vitro

In brain slices, the effects of induced ﬁelds can be studied with

exquisite control, since all synaptic signaling can be blocked

pharmacologically55. Most studies apply constant ﬁelds across

parallel wires outside the slice. This spatially diffuse stimulation

differentially affects the neuronal compartments (e.g., soma,

apical dendrites), producing complex effects23. In vitro recordings

of rat hippocampal and neocortical pyramidal cells show that DC

electric ﬁelds of 1 V/m can polarize the soma of pyramidal neu-

rons by ~0.2 mV.

Yet, extracellular electric ﬁelds abound in the brain22. Local

electric ﬁelds (> 0.5 V/m) applied in vitro with a micropipette

near layer 5 pyramidal cell dendrites and soma induce small

intracellular voltage ﬂuctuations (e.g., 0.2 mV) and may phase-

lock the spikes to the low-frequency (1–30 Hz) oscillating external

ﬁeld without affecting overall spiking rate56. Thus, under idea-

lized conditions, very weak but localized extracellular ﬁelds can

bias neuronal activity (Fig. 3). Spike timing is highly sensitive to

small, persistent oscillations that act throughout a volume. This

voltage ﬂuctuation is comparable to intrinsic, non-synaptic,

internally generated noise in layer 5 pyramidal neurons (0.2–0.4

mV)57 and is much smaller than synaptic background activity

in vivo33,58. For example, hippocampal theta oscillations, for

instance, induce ~4 V/m electric ﬁelds across the CA1 pyramidal

layer, while hippocampal sharp waves induce 5–15 V/m39.

Endogenous ﬁeld strengths associated with slow oscillations in

the neocortex are 1–2 V/m45. Whether weak applied electric ﬁelds

can overcome such strong endogenous ﬁelds remains an impor-

tant experimental question.

AC ﬁelds of sufﬁcient strength applied at low frequencies

(< 10 Hz) can modulate ﬁring rate periodically by the same

mechanisms as DC ﬁelds59. For higher AC stimulation fre-

quencies, the induced effects are diminished; for example, somatic

polarization is reduced by ~70% when a 50 Hz AC stimulation

induces a 1 V/m ﬁeld, because the membrane cannot follow the

rapid ﬂuctuations in the electric ﬁeld60. The oscillatory ﬁelds may

Control

Extracellular stimulation

Spike field

coherence (%)

Spike field

coherence (%)

0 0.2 0.4 0.6

0 2.1 4.2

V amplitude (mV)

field strength (mV/mm)

V amplitude (mV)

field strength (mV/mm)

6.4

0 0.2 0.4 0.6

0 2.1 4.2 6.4

50 mV

50 µm

1 mV

Fig. 3 Field-entrainment of spikes under idealized conditions in vitro. Synaptic transmission was blocked pharmacologically. aFour neurons with somata

located within 100 μm of tissue were patched with intracellular electrodes (blue). Seven extracellular electrodes monitored extracellular voltage (Ve)

ﬂuctuations (magenta). An extracellular stimulation electrode (S1) was placed 50–80 μm from the recorded somata. bEach of the four intracellularly

recorded neurons were depolarized to induced spiking. Spiking in the absence (top traces) and in the presence of extracellular stimulation (magenta;

100 nA at 1 Hz; bottom traces) is shown. cSpike ﬁeld coherence (circles, mean; error bars, s.e.m.) between spikes and extracellular Veis shown during

1 Hz extracellular stimulation (black) and control condition (cyan; circles indicate mean Ve amplitude at the soma and error bars indicate s.e.m.) as a

function of stimulation strength. Asterisks indicate statistical signiﬁcance of the spike-ﬁeld difference between control and extracellular stimulation.

dSpike-spike coordination (spike-ﬁeld coherence for two simultaneously occurring spikes; essentially spike synchrony among neurons) during 1

Hz extracellular stimulation (black) and control (cyan) condition. Note that stronger ﬁelds are needed for coherent entrainment of neuronal spikes across

the four neurons (d) than for inducing spike-ﬁeld coherence for each neuron separately (c). Figure reproduced with permission56

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not affect the overall ﬁring rate but can modulate the timing of

ongoing spikes56,59 (Fig. 3). AC stimulation at a frequency

matching the resonant neuronal properties can induce cumulative

effects over multiple cycles43,45,59–62. Under such ideal condi-

tions, AC ﬁelds as low as 0.2–0.5 V/m can shift spike

timing23,43,59,60. Higher stimulation frequencies require stronger

currents to bias spike-LFP coupling (> 0.7 V/m induced ﬁeld at 1

Hz and > 5 V/m at 30 Hz56,39, Fig. 3), due to the frequency ﬁl-

tering properties of the neuronal membrane63. One caveat of

these in vitro studies is that pharmacologically or intracellularly

induced oscillations are much more regular than in vivo oscilla-

tions19. Overall, in vitro studies have laid the biophysical foun-

dation for TES, providing quantitative relationships between the

effective magnitude of voltage gradients for both V

and spiking

activity. These experiments have also clariﬁed the geometric

relationship between the vectorial ﬁeld and neuronal morphology

and soma-dendritic orientation. However, these studies do not

reveal how applied current affects neurons when applied through

the skin, subcutaneous tissue, skull, dura and cerebrospinal ﬂuid

in the living animal. For a detailed summary of in vitro experi-

ments measuring acute physiological changes during TES, see

Supplementary Table 1.

Acute effects of external electric ﬁelds in rodents

In rodent experiments, electric ﬁelds are often applied with

electrodes placed on the skull, the dura mater, or directly on the

brain surface. Often, a saline-ﬁlled cup is applied at various epi-

cranial locations with a return electrode on the thorax or the

contralateral hemisphere. Several in vivo studies have found a

dose-dependent relationship between the induced electric ﬁeld

and spiking rate24,34,35,40, transmembrane potential and, at

higher stimulation intensities, on the LFP25,35,39. Applied electric

ﬁelds can alter neuronal excitability64 and evoked responses64,65

in a polarity-speciﬁc manner.

However, rodent studies typically use ten-fold stronger current

intensities compared to human studies66. Across the 28 rodent

experiments reviewed67 (Supplementary Table 2), the induced

intracranial ﬁelds averaged 6.8 ± 3.8 V/m (n=11, ten epicranial

and 1 subdural studies), compared to < 1 V/m measured in con-

ventional human TES studies19,68,69. While stimulating transcra-

nially in rats, the lowest electric ﬁeld sufﬁcient to affect the timing

of spiking activity in widespread cortical and hippocampal areas

was ~1 V/m; higher intensities were required to reliably affect LFP

and the membrane potential in intracellularly recorded neurons

in vivo35,40.Higherﬁeld intensities were also required in urethane-

anesthetized rats to affect LFP oscillations70,71. Similarly, applied

currents have terminated thalamocortical spike and wave patterns

in rodents (1.5–2 mA, applied to skull)54,72 or triggered paw

movement (0.25 mA and 0.9 mA)34 and modulated endogenous

slow wave initiation and propagation patterns (~3 mA /mm2)73.In

summary, rodent stimulation studies demonstrate physiological

effects on spike timing, LFP oscillations, and terminating seizure

patterns, but applied currents were several-fold stronger than the

currents expected to penetrate the human brain using TES. For a

detailed summary of in vivo experiments measuring acute phy-

siological changes during TES, see Supplementary Table 2.

Immediate electrophysiological effects of TES in primates

Non-human primates permit TES investigations using a relatively

large head with a gyrated cortical surface. The variable anatomy,

including thick skull and large musculature, can result in a wide

range of ﬁeld strengths across studies and even across individuals.

Opitz et al.69 measured ﬁeld strengths in two anesthetized cebus

monkeys with small round scalp electrodes (3.14 cm2) over the

left occipital and frontal cortices stimulated with 1–2 mA. The

median induced electric ﬁelds were 0.21 V/m (strongest 0.36 V/

m) in a male monkey (4.1 kg) and 0.39 V/m (strongest 1.16 V/m)

in a female monkey (2.9 kg). The weaker effects in the male likely

reﬂected the larger head musculature that shunted much of the

applied current.

Krause et al.74 studied the effects of tDCS with intracranial

electrodes in right prefrontal and left inferotemporal cortices in

macaque monkeys performing an oculomotor foraging task. Based

on a ﬁnite-element model75, 2 mA anodal stimulation applied to the

right prefrontal region induced ﬁeld strengths between 0.4–0.7 V/m.

Although tDCS did not affect the spontaneous or task-related ﬁring

rates of isolated single units or multi-unit clusters, LFP power in the

1–15 Hz band increased ten-fold during DC stimulation, and

coherence within the prefrontal array increased at all frequencies

from 2–100 Hz. However, the changes in spike frequency or spike-

ﬁeld coherence in areas with stronger ﬁelds (up to 1 V/m) but

outside the recording area, could not be ruled out.

Kar et al.76 delivered tACS of 1 mA peak amplitude at 10 Hz

frequency through scalp electrodes placed anterior to the vertex

and lateral to the middle temporal area (MT). In one monkey, the

induced ﬁeld was 0.12 V/m at closely spaced electrodes (0.5 mm)

in the recorded MT area. Spiking activity during the stimulation

was not reported, but a reduction in spike adaptation to the visual

input after tACS offset was observed.

In a dose-ranging tDCS experiment on motor control, Lee et al77.

applied anodal stimulation over primary motor cortex (with cathode

at the vertex) to determine the threshold to elicit a muscle twitch in

sedated macaques. Between 50–120 mA (~35–55 V/m electric ﬁelds

in the motor cortex) were needed to trigger a visible twitch.

In summary, primate models offer the advantage of testing TES

in a larger head model with a gyrated cortical surface. The few

primate studies which have been performed to date employ dif-

ferent montages and measurement techniques. Compared to the

rodent models, primate experiments are limited by weaker

induced ﬁelds and proportionately less cortical recording cover-

age. Primates with large heads, thick skulls, and greater muscu-

lature have greater shunting, or current loss away from the brain,

and require larger current intensities to achieve comparable

electric ﬁeld strengths to those in rodent brains. These differences

highlight the critical need to match intracerebral ﬁelds rather

than stimulation parameters across species and experiments.

Ex vivo human studies

Translating the results of in vitro and in vivo animal experiments

to humans is confounded by complexities of brain and head

anatomy. Neurons in highly gyrated cortices of higher primates

have variable alignments even on the convexity29,78, in contrast to

those of lissencephalic rodents which are mostly perpendicular to

the skull surface. Since entrainment efﬁcacy of neurons depends

on how polarized neurons align with the direction of the electrical

ﬁeld, TES of human cortical gyri may lead to unpredictable

effects. Further, safety considerations require TES application

through the hair, skin, and skull. In contrast, few animal

experiments applied TES through the scalp35,69,74,76. Using

transcranially applied stimulation, only a small fraction of the

applied current enters the brain: most is lost through the skin,

subcutaneous soft tissue, and the skull35 (Fig. 4a). One study

conducted in rodents and human cadavers demonstrated that >

75% of applied TES current is lost through shunting35, although

the shunting effects differ between humans, nonhuman primates

and rodents in unknown ways.

Human cadavers yield insights regarding conductivity and

anisotropy. Multiple intraparenchymal, three-dimensional mea-

surements of the electric ﬁeld distribution can be obtained and

multiple stimulation parameters can be tested in the same cadaver

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(Fig. 4b, c). Such empirical measurements help determine the

basic biophysical tissue properties and help model effects of TES

into the brain parenchyma79–81 (Fig. 4d–f). Intracerebral electric

ﬁelds were measured in intact cadaver brains at 198 sites in a

three-dimensional grid, while applying stimuli that varied in

frequency, intensity, phase relationship, electrode location, and

size35. The authors concluded that scalp, skull, brain, and cere-

brospinal ﬂuid behave as ohmic conductors. In other words,

induced ﬁelds increased linearly with stimulation intensity, but

were independent of stimulation frequency82. The comparison of

transcutaneous, subcutaneous and epidural stimulations of the

cadaver brain led to the conclusion that the bilateral transcuta-

neous stimulation of the cadaver heads with traditional montages

and intensity (peak 1 mA) induced only ~0.2 V/m ﬁeld in the

brain35. Of note, death imparts profound changes in the bio-

physical properties of brain tissue, limiting a direct ex vivo to

in vivo comparison83.

In vivo human studies

A critical question is the magnitude of the electric ﬁeld reaching

the brain when using conventional TES, applied transcutaneously

at peak intensity currents of 1–2 mA, because ﬁeld strength

constrains the expected nature of the physiological changes

(Fig. 2). The main barrier for TES to reach the brain is the skull’s

high resistance (~160 Ωm) combined with the low resistance of

the scalp (~2 Ωm)80. A large fraction (up to 75%) of the current

seeks the path of least resistance and shunts across the scalp35.

Three independent studies using intracranial electrodes in epi-

lepsy patients undergoing surgical evaluation demonstrated that

maximal electric ﬁelds at the cortical surface under the electrodes

were < 0.5 V/m for 1 mA peak intensity currents68,69,84.

Can such weak electric ﬁelds reaching the human brain induce

changes in neuronal networks, as measured by changes of the

LFP? Oscillations are ubiquitous in the human brain, ranging

from ultraslow (0.05 Hz) to ultrafast (500 Hz), with speciﬁc

oscillation frequencies characterizing different arousal states or

cognitive processes and coordinating activity between local and

distant brain regions85. A leading hypothesis about the behavioral

effect of tACS is that the applied stimulation frequency matching

the dominant network oscillation entrains and augments endo-

genous rhythms37,38,62,86–89, such as gamma60,89,90, beta91,

alpha46, theta92, and slow frequency oscillations40,45,93.

Whether the weak electric ﬁelds resulting from TES at con-

ventional intensities (1–2 mA peak) can entrain neuronal oscil-

lations is technically difﬁcult to assess. One technical challenge is

that the magnitude of the stimulation artifact is dramatically

larger than the magnitude of the endogenous oscillation, making

artifact rejection difﬁcult. To illustrate, supposing the use of a

10 Hz tACS waveform to entrain endogenous alpha oscillations,

the amplitude of alpha waves is ~ 100 µV over the parietal-

occipital lobes, whereas the artifact induced by a 2 mA tACS

stimulus can exceed 1 V (~1000x greater). Therefore, even if

99.9% of the artifact is removed, the remaining 0.1% of the

artifact would be as large as the endogenous alpha rhythm.

Further, the stimulus waveform can be distorted, resulting in

multiple harmonics of the applied signal. Due to non-linearities

and instability of the stimulation waveform during the experi-

ment, the waveform of the stimulation artifact and its harmonics

across trials cannot simply be subtracted from the resulting EEG

recordings. While artifact rejection algorithms can clean the

recorded signals, artifact-free brain activity is unlikely to be

recovered when the stimulation frequency matches the endo-

genous oscillation frequency94. Another challenge is the

ab c

de f

Skin

Skull

Electric field (mV/mm)

Relative shunting effect

+++++++

1.5

0.5

Stimulation

electrode Skin Skull Brain

Distance from skin surface (mm)

0.2

0.1

00 0.5 1 1.5 6

0.5

10 100 1000

Stimulus frequency (Hz) Stimulus intensity (mA)

10 50 100

Stimulus intensity (µA)

200

6 × 10 mm

5 × 15 mm

Fig. 4 Current loss of TES in rodents and in human cadaver brains. aCompared to subcutaneous stimulation (red), transcutaneous stimulation (blue)

generated several-fold weaker electric ﬁelds in a rodent model. bSchematic of the experimental arrangement for transcutaneous, subcutaneous, and

epidural stimulation in cadavers, in a coronal plane. cPhotograph of the cadaver skull with drilled holes and inserted matrix of recording electrodes.

Stimulation electrodes, marked by blue and red circles for negative and positive polarity, respectively, were ﬁxed to the skull. dEffect of stimulus frequency

on intracerebral voltage gradients. Stimulus frequency between 5 and 1000 Hz has a minor effect on intracerebral gradients. eExtrapolation from

measurements in human cadavers (blue crosses) suggests that approximately 6 mA current applied across the skin would induce 1 V/m intracerebral

electric ﬁeld (blue open circle). fAttenuation of charge ﬂow (red line) through scalp (pink), skull (yellow), and brain (dark pink), as measured in human

cadaver heads. Figure adapted from Figs. 1,4,5in Voroslakos et al., (2018)35, under the Creative Commons License

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saturation of recording ampliﬁers, which precludes analysis of the

endogenous LFP during stimulation.

Besides neurophysiology, other experimental measures of TES

immediate effects include blinded subject reporting, TMS-evoked

motor evoked potential (MEP), and fMRI. Feurra et al.49 applied

at 1.5 mA anodal current at varying frequencies of (2–70 Hz) over

somatosensory cortex and asked subjects to report tactile sensa-

tion in the contralateral hand. While no sham or control sti-

mulation site was included, during one of the two replications,

subjects reliably reported sensation during alpha (10–14 Hz) and

high gamma (52–70 Hz) frequency stimulation. These occasional

behavioral effects of TES may reﬂect stochastic resonance (Fig. 3).

A study of TMS-evoked MEPs during tACS (1 mA peak-to-

peak) at different frequencies (theta, alpha, beta, and gamma) over

the primary motor cortex during rest and during a motor imagery

task found MEPs were greatest during beta frequency tACS at rest,

but during theta–tACS during motor imagery38. Guerra et al.51,

found beta frequency (1 mA peak-to-peak, 20 Hz) tACS stimula-

tion acutely modulated the MEP amplitude in a phase-dependent

manner; however another experiment37 (1.5 mA peak-to-peak)

did not ﬁnd phase-dependent modulation of corticospinal

responses using low-frequency tACS (0.8 Hz) or tDCS super-

imposed with 0.8 Hz. An fMRI study applied 20 Hz tACS stimu-

lation (1 mA peak-to-peak) over the primary motor cortex (M1)

found enhanced local connectivity within M1, without changing

the overall local activity or long-range connectivity within the

default mode network95. While these TMS and fMRI ﬁndings are

consistent with a rhythm-resonance mechanism (i.e., 20 Hz

modulation of resting beta frequency in motor cortex; Fig. 2), a

peripheral contribution remains possible. Both consciously

detected and subthreshold (unconscious) sensory stimuli can

inﬂuence neocortical activity96,97.

Epilepsy patients undergoing invasive monitoring offer the

opportunity to measure and analyze endogenous oscillations

during TES and thus directly monitor brain responses, since

intracranial signals are an order of magnitude larger than those

recorded from the scalp. The effects of tACS (0.75 Hz and 1 Hz)

during NREM sleep and waking rest were assessed in epilepsy

surgery patients at standard stimulation intensities (up to 2.5 mA

peak to peak; maximum induced ﬁeld: 0.43 V/m). During NREM

sleep, slow oscillations (~1 Hz) strongly entrain spindle activity in

the 10–15 Hz range. This provides the opportunity to test whe-

ther endogenous slow-wave rhythms can be entrained with low

frequency (0.75 Hz or 1 Hz) tACS, while measuring entrainment

in a different frequency band that is largely uncontaminated by

stimulation artifacts. While spindle and gamma activity robustly

entrained to the phase of the endogenous slow oscillation, low-

frequency tACS failed to entrain spindle or gamma activity at

over 1000 electrode sites measured in patients during NREM

sleep. Likewise, no entrainment of gamma or theta activity was

observed during waking rest19,98.

Instead of entrainment, TES-phase/EEG-amplitude coupling

can also be examined with scalp recordings. This approach was

validated by concurrent unit recordings in rat experiments54.In

agreement with the intracerebral recordings19, no detectable

effect was obtained on the scalp EEG when TES was applied at <

2.5 mA in healthy subjects35. However, reliable tACS phase

modulation of the amplitude of alpha rhythms was present when

intensities exceeded 4.5–6 mA. The effect was speciﬁc for neu-

ronal stimulation of cortical neurons because alpha amplitude

enhancement over the left and right occipital cortex occurred in

phase with alternating the anodal stimulation. Furthermore, to

rule out peripheral contributions, control experiments applying

stimulation to the abdomen did not produce an effect on alpha

activity.

Novel TES methods

Current applied through the scalp stimulates electrically sensitive

elements from the scalp surface to the brain. These peripheral

side effects, including stimulation of cranial nerves, retina, and

vestibular system, limit the maximum tolerable dosing in humans

using traditional TES approaches. Currents exceeding 1–2mA

(depending on electrode type) can cause itching, burning sensa-

tion, pain at the skin under and around the electrodes99.

The next generation of TES technologies should make three

advancements: (1) delivery of stronger currents to the brain while

minimizing peripheral and indirect effects; (2) simultaneous sti-

mulation and recording of brain activity for quantitative mea-

surements of TES-induced effects; and (3) targeting of speciﬁc

rhythms through closed-loop stimulation of brain areas, includ-

ing deep brain structures.

Multi-electrode stimulation is one potential method to increase

current density and focality of stimulation delivered to the brain

surface. The strongest transmembrane polarization is expected to

build up where electric ﬁelds overlap inside the head, whereas the

intensity of local scalp stimulation is divided proportionally by

the number of stimulation electrode pairs. The approach is

similar to previous efforts which used multiple small electrodes to

optimally target speciﬁc brain areas100.

Two other approaches attempt to increase the brain to scalp

stimulation ratio. The ﬁrst is temporal interference stimulation.

First introduced for stimulating peripheral nerves and brain101,

temporal interference is now routinely used in physical ther-

apy102. When applied to the mouse brain, intersecting 2 kHz and

2.01 kHz sinusoidal waveforms yielded a 10 Hz amplitude mod-

ulation of the LFP34. Because the high-frequency stimulus exceeds

the time constant of the peripheral nerve membrane, the fast

alternating current may reduce skin sensations and avoid retinal

responses, while the interfering signals in the brain are expected

to be strong enough to modulate neuronal ﬁring. The second

approach, ‘intersectional short pulse‘(or ISP) stimulation, uses

multiple electrode pairs35. This time-multiplexing method

exploits the time integrating property of the neuronal membrane

(i.e., the membrane time constant of cortical neurons is ~30 ms),

by applying currents that switch every 60 µs between the electrode

pairs. The strongest transmembrane charge will build up where

successively induced electric ﬁelds overlap inside the head,

whereas the intensity of local scalp stimulation is divided pro-

portionally by the number of stimulation electrode pairs. Again,

the more electrode pairs are used, the greater the potential to

generate brain focal stimulation while minimizing stimulation of

the scalp to reduce skin sensations78,100. Initial studies using

temporal interference and ISP show increased spatial targeting in

animal models, but further analysis and reﬁnements of these

techniques are necessary.

The application of high-frequency pulses avoids the saturation

of recording ampliﬁers and allows for the simultaneous mea-

surement of the direct physiological effects of tES in humans35.

Ampliﬁer modiﬁcations, such as front-end subtraction of the

applied tES waveform can further reduce induced artifacts. Such

innovations are essential to directly quantify the physiological

responses of neuronal circuits.

Recommendations for future experiments

Although the lasting effects of stimulation are the main purpose

of most clinical trials103,104, our review focused on the immediate

physiological effects of TES on spikes and network dynamics. A

more accurate and sophisticated understanding of physiology,

grounded in empirical measurements, will improve design and

execution of future TES experiments, with more potent and

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consistent clinical beneﬁts. Below, we offer a list of tasks for

future TES research.

Exploration of peripheral and non-neuronal mechanisms of

TES. It is tacitly or explicitly assumed that behavioral and clinical

effects of TES are mediated by directly affecting neuronal activity

in the brain. However, behavioral and cognitive changes in

response to scalp electric stimulation may be mediated by other

effects as well. Electric ﬁelds affect the excitability of sub-

cutaneous nerves which signal to the brain. Even when the subject

does not report a conscious experience of TES, sensory stimula-

tion can still indirectly affect brain circuits97,105. Therefore,

control experiments that measure the conscious and subconscious

effects of sensory stimulation should be included in future studies.

This can be achieved by including an “active control,”such as

stimulation of the neck or abdominal areas35 or application of

TES to another region of the brain106. In addition, applying

topical anesthesia to the scalp under the electrodes and testing

varying intensities of skin stimulation could exclude or char-

acterize sensory contributions.

Long-lasting TES effects can be indirectly mediated by non-

neuronal mechanisms as well, including trophic factors107,

neurotransmitter metabolism51,108 glia109,110, neuroendocrine

system111,ﬁbroblasts112 lymphocytes, and other electrically

charged immune system components113. These potential non-

neuronal effects should be considered with low-intensity scalp

stimulation, which may be too weak to induce the necessary

electric ﬁeld strengths to instantaneously affect neuronal activity.

These indirect effects may play a role even when neuronal activity

is directly affected by stronger TES.

Targeting neural circuits. Growing evidence, summarized above,

suggests that TES applied at ± 1 mA peak intensity (2 mA peak to

peak) generates < 0.5 V/m electric ﬁelds in the human brain. This

is sufﬁcient to generate 0.1–0.2 mV changes in the membrane

potential of cells within the stimulated area. As these changes are

signiﬁcantly lower than the 20 mV depolarization required to

bring a neuron from its resting potential to spike threshold

in vitro, TES is unlikely to directly elicit changes in spiking

activity. Instead, weak induced ﬁelds may be more effective when

used to bias or augment ongoing rhythms instead of introducing

new activity patterns. Applying current at the optimal phase of

endogenous rhythms in a closed-loop system may be most

effective54. However, such responsive methods require character-

ization of the affected circuitry and continuous monitoring

and adjustment of the relevant rhythms114. This may be achieved

with weak electric ﬁelds but other applications may require

higher ﬁeld strengths. For example, prompt control of spiking

activity (e.g., to terminate a seizure) may require ﬁeld strengths >

5 V/m72.

Modeling for spatial targeting and to increase replication

across subjects and studies. Individual variations in neuroa-

natomy (scalp, muscle, and skull thickness) can signiﬁcantly alter

the strength and distribution of the induced electrical ﬁeld in

humans68,98,115–117 and experimental animals75,77, and thus may

account for inconsistent behavioral results in human TES

experiments. This is exempliﬁed by Fig. 5, which compares two

individual models, with the same surface electrode montage but

different head anatomy (Fig. 5a, b, created using previously

published data and methods118,119). Differences in skull thickness

and cerebrospinal ﬂuid volume in posterior regions lead to dif-

ferent ﬁeld distributions (Fig. 5a, b).

Computational models of current ﬂow have been continuously

reﬁned over the last decade78,100,116,117,120–122. Recent head

models can improve spatial targeting by guiding stimulation

electrode placement (Fig. 5c). These models are based on

segmentation of tissue (at 1 mm3resolution) into compartments

of differing electrical conductivities, including skin and other soft

tissues, skull, gray matter, white matter, ventricles, and cere-

brospinal ﬂuid. Models indicate that focal stimulation of a few

centimeters may be achieved at the cortical surface100, generally

with a trade-off between focality and intensity of stimulation

(Fig. 5). Deep targets may be reached at relatively high ﬁeld

intensities when adjacent to CSF-ﬁlled ventricles, which can guide

currents deep into the brain68.

Computational models can help optimize electrode locations

for maximal stimulation of a desired brain target100. Individual

MRI head anatomy combined with toolboxes such as ROAST,

and SimNIBS, and SCIrun can deﬁne ﬁeld distribution for this

purpose. When an individual’s head MRI is not available,

validated and calibrated universal head models can help

reproduce in vivo intracranial measurements118,119,123. Further-

more, multielectrode montages can be optimized to engage local

and network level targets, as demonstrated by a technique

combining electric ﬁeld modeling and cortical networks derived

from PET or resting state functional connectivity MRI124.

Human TES experiments typically report the stimulation

protocols by reporting the stimulating electrode positions (e.g.,

“anode at F8”or “over left dorsolateral PFC”) and current

intensities (e.g., “2mA”). These speciﬁcations describe how the

experiment was designed and performed, but they only indirectly

deﬁne the induced electrical ﬁeld strength and distribution.

Reporting induced ﬁeld estimates from head models would help

relate behavioral and clinical reports to underlying neural

mechanisms. When the individual MRI head is available,

subject-speciﬁc estimates of the induced ﬁeld strength should

be included as a covariate in analyses of its behavioral or neural

effects. Intensity-response curves, inverted polarity stimulations

and skin stimulations far from the desired target location may

distinguish between direct brain-stimulation and peripheral

effects. Measurements or estimates of the electric ﬁeld strength

are included in some recent human and large animal studies but

are missing from most rodent studies. Reporting ﬁeld magnitudes

is important for animal studies where variable head size and

anatomy can strongly affect ﬁeld magnitudes. These values would

provide a critical translational scaling metric to facilitate

comparisons with human and animal studies and should be

included in future publications.

Hardware and signal processing issues. The simultaneous

measurement of physiological activity (EEG, ECoG) during tACS

is complicated by stimulation artifacts several orders of magni-

tude larger than intrinsic brain activity (1–100 µV). When brain

activity and stimulation are recorded simultaneously, special care

should be taken to (1) avoid saturation of the recording ampliﬁer

during experiments, and (2) subtract stimulation artifacts from

the measured signal. Saturation can be avoided by using high-

quality ampliﬁers with sufﬁcient input dynamic range (e.g. an

ampliﬁer with dynamic range of ± 100 mV can capture the full

stimulation artifact).

Artifact rejection methods initially suggested for scalp EEG87

are highly unlikely to fully recover artifact-free brain activity (see

above)94,125. Therefore, when using tACS stimulation, it is

difﬁcult to analyze online neural responses at the same frequency

in which stimulation is applied (e.g., increases in alpha

oscillations during 10 Hz tACS stimulation). Analysis should

target frequencies well away from the stimulation frequency and

its harmonics. Measurements using phase-amplitude coupling or

single-unit recordings may also be used when available.

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DC stimulation artifacts pose less of an issue during signal

processing as hardware ﬁlters will typically remove any DC offset

(avoiding ampliﬁer saturation). However, EEG recordings in

humans are affected by artifacts in the 1–15 Hz frequency band

due to heartbeats and eye-blink125,126. The effect is most

prominent in frontal locations. In addition, care should be taken

to avoid motion of the subject and stimulation electrodes,

electrical noise injected into the system is reduced by using high-

quality (i.e., narrow band) stimulation devices, and environ-

mental noise (ensure adequate electrical isolation19,68. Control

experiments, e.g., using a phantom head model, are needed to

separate TES-related artifacts from the induced neural activity.

Data sharing standards. Because different devices use different

conventions, it is critical to specify whether tACS amplitudes

describing the absolute magnitude (i.e., the amplitude of one

phase), the peak-to-peak amplitude, or another form of para-

meterization. Shared data and analysis methods can facilitate

coordinated community efforts and metanalysis. Combining

many data sets may offer novel insights and interpretations (e.g.,

https://www.nwb.org/). Further, given the artifact rejection

methods described above, sharing raw EEG data sets would

enhance replication of the signal processing pipeline. Sharing

analysis software packages will facilitate cross-validation of results

across studies.

Conclusions

A more accurate and sophisticated understanding of TES phy-

siology, grounded in empirical measurements, will improve the

design and execution of neurostimulation experiments, yielding

more robust and consistent clinical beneﬁts. While the authors of

this review share a consensus on experimental recommendations,

we acknowledge a controversy within the TES ﬁeld and amongst

ourselves as to whether the attenuated electrical ﬁelds that reach

the human brain with conventional protocols can directly affect

neurons and neuronal networks. While direct neural mechanisms

have been measured with exquisite experimental control in vitro

and in vivo models, whether these insights translate to humans is

uncertain. We have highlighted challenges in translating

mechanistic insights from experimental models to humans,

including (1) the interaction of the applied external ﬁeld with

competing or cooperating network oscillations when comparing

in vitro to in vivo studies; (2) external ﬁelds applied to the folded

cortical surface produce more variable and unpredictable effects

in larger animals (including humans) compared to rodent and

in vitro models; (3) the large human head and the low resistance

scalp shunt most applied current, with much smaller fraction of

the applied current reaching the cortical surface.

The weak induced electric ﬁelds reaching the human brain

contrast with the numerous behavioral and clinical effects

reported. We should also consider how TES can affect brain

activity indirectly, including activation of afferent nerves127,

Injected current

(mA)

Electric field

(V/m)

–1

–2

0.6

0.4

0.2

ab c

Fig. 5 Individualized models of transcranial electrical stimulation for two subjects with variable electrode placements. aModel of Subject 1, with 2 mA

current injected at electrode Fp1 and return from electrode P3. bModel of Subject 2 with the same electrode conﬁguration. cModel of Subject 2 with

another electrode conﬁguration attempting to achieve more focal stimulation. Note that stimulation is more focal but achieves weaker ﬁelds compared to

b, due to increased current shunting through the skin between near-by electrodes. Electrode montages in band care obtained by a numerical optimization

algorithm that attempts to achieve maximal intensity (b) or maximal focality (c) for the location indicated by a black circle. The current-ﬂow models were

generated from previously published data118 and methods119. We used ROAST, a toolbox for realistic current-ﬂow models of the human119

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retina and the vestibular apparatus42, astrocytes, perivascular

elements, and glial activation109,110, as well as through placebo

effects128. Both tACS and tDCS may also induce cumulative or

longer-term effects via unknown mechanisms that merit further

exploration. Future human behavioral trials should control for

sensory contributions with approaches such as topical anesthesia,

or by using sensory controls such as stimulation away from the

desired targets.

Novel stimulation methods that safely induce higher brain to

scalp electric ﬁeld ratios are needed. Existing experimental tech-

niques, such as temporal interference stimulation and intersec-

tional short pulse stimulation delivering stimulation at high

frequencies (> 1 kHz), require further testing in both experi-

mental animals and humans. These and related methods, such as

multielectrode TES78,100, may better target brain structures

compared to conventional electrode montages. Closed-loop

techniques may enhance the efﬁcacy of TES via resonant mod-

ulation of native brain rhythms. In selected cases, supported by

experimental ﬁndings and human head-based modeling, sub-

cutaneous arrays or electrode plates inserted below the skin may

provide superior efﬁcacy, similar to techniques to treat head-

ache129 and facial pain129,130 by stimulating peripheral nerves.

With further development, TES could become a leading tool for

chronic, on-demand, at-home treatment of many neuropsychia-

tric and neurological diseases.

Received: 26 April 2018 Accepted: 18 October 2018

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Acknowledgements

We thank NYU Finding a Cure Against Epilepsy and Seizures (FACES) for sponsoring

the Minisymposium Current state of Transcranial Electrical Stimulation: Progress &

Challenges, on December 18, 2017 where the discussions contained in this manuscript

arose. In addition, A.L., S.H., O.D., and G.B. receive support from R01 MH 107396.

Author contributions

A.L. and G.B. have composed and written the review with contributions from M.V., G.K.,

S.H., M.K., Y.H., A.O., A.M., C.P., B.K., A.B., L.P., L.M. and O.D.

Additional information

Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-

018-07233-7.

Competing interests: A.B. is the founder and owner of Amplipex and Neunos LLCs,

which manufacture biosignal ampliﬁers and stimulator devices. A.B. and G.B. have ﬁled a

patent application about the ISP method. A.O. is an inventor on patents and patent

applications describing methods and devices for noninvasive brain stimulation. B.K. is a

paid consultant for Aqeel, LLC, which develops transcranial stimulation technology. L.P.

has shares in Soterix Medical Inc., which develops transcranial stimulation

technology. The remaining authors declare no competing interests.

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Supplementary Material

Data

November 2018

Anli Liu · Mihály Vöröslakos · Greg Kronberg · Simon Henin · Gyorgy Buzsáki

Temporal interference stimulation disrupts spike timing in the primate brain

Preprint

Full-text available

Sep 2023

Electrical stimulation can regulate brain activity, producing clear clinical benefits, but focal and effective neuromodulation often requires surgically implanted electrodes. Recent studies argue that temporal interference (TI) stimulation may provide similar outcomes non-invasively. During TI, scalp electrodes generate multiple electrical fields in the brain, modulating neural activity only where they overlap. Despite considerable enthusiasm for this approach, little empirical evidence demonstrates its effectiveness, especially under conditions suitable for human use. Here, using single-neuron recordings in non-human primates, we show that TI reliably alters the timing of spiking activity. However, we find that the strategies which improve the focality of TI — high frequencies, multiple electrodes, and amplitude-modulated waveforms — also limit its effectiveness. Combined, they make TI 80% weaker than other forms of non-invasive brain stimulation. Although this is too weak to cause widespread neuronal entrainment, it may be ideally suited for disrupting pathological synchronization, a hallmark of many neurological disorders.

Integrating electric field modeling and pre-tDCS behavioral performance to predict the individual tDCS effect on visual crowding

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Sep 2023
J NEURAL ENG

Objective. Transcranial direct current stimulation (tDCS) has been broadly used to modulate brain activity with both bipolar and high-definition montages. However, tDCS effects can be highly variable. In this work, we investigated whether the variability in the tDCS effects could be predicted by integrating individualized electric field modeling and individual pre-tDCS behavioral performance. Approach. Here, we first compared the effects of bipolar tDCS and 4 × 1 high-definition tDCS (HD-tDCS) with respect to the alleviation of visual crowding, which is the inability to identify targets in the presence of nearby flankers and considered to be an essential bottleneck of object recognition and visual awareness. We instructed subjects to perform an orientation discrimination task with both isolated and crowded targets in the periphery and measured their orientation discrimination thresholds before and after receiving 20 min of bipolar tDCS, 4 × 1 HD-tDCS, or sham stimulation over the visual cortex. Individual anatomically realistic head models were constructed to simulate tDCS-induced electric field distributions and quantify tDCS focality. Finally, a multiple linear regression model that used pre-tDCS behavioral performance and tDCS focality as factors was used to predict post-tDCS behavioral performance. Main results. We found that HD-tDCS, but not bipolar tDCS, could significantly alleviate visual crowding. Moreover, the variability in the tDCS effect could be reliably predicted by subjects' pre-tDCS behavioral performance and tDCS focality. This prediction model also performed well when generalized to other two tDCS protocols with a different electrode size or a different stimulation intensity. Significance. Our study links the variability in the tDCS-induced electric field and the pre-tDCS behavioral performance in a visual crowding task to the variability in post-tDCS performance. It provides a new approach to predicting individual tDCS effects and highlights the importance of understanding the factors that determine tDCS effectiveness while developing more robust protocols.

Growing placebo response in TMS treatment for depression: a meta-analysis of 27-year randomized sham-controlled trials

Article

Full-text available

Sep 2023

Transcranial alternating current stimulation in affecting cognitive impairment in psychiatric disorders: a review

Article

Full-text available

Sep 2023
EUR ARCH PSY CLIN N

Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that, through its manipulation of endogenous oscillations, can affect cognition in healthy adults. Given the fact that both endogenous oscillations and cognition are impaired in various psychiatric diagnoses, tACS might represent a suitable intervention. We conducted a search of Pubmed and Web of Science databases and reviewed 27 studies where tACS is used in psychiatric diagnoses and cognition change is evaluated. TACS is a safe and well-tolerated intervention method, suitable for multiple-sessions protocols. It can be administered at home, individualized according to the patient'’s anatomical and functional characteristics, or used as a marker of disease progression. The results are varying across diagnoses and applied protocols, with some protocols showing a long-term effect. However, the overall number of studies is small with a great variety of diagnoses and tACS parameters, such as electrode montage or used frequency. Precise mechanisms of tACS interaction with pathophysiological processes are only partially described and need further research. Currently, tACS seems to be a feasible method to alleviate cognitive impairment in psychiatric patients; however, a more robust confirmation of efficacy of potential protocols is needed to introduce it into clinical practise.

Mechanisms of Action of Noninvasive Brain Stimulation with Weak Non-Constant Current Stimulation Approaches

Article

Full-text available

Sep 2023

Objective: Non-constant current stimulation (NCCS) is a neuromodulatory method in which weak alternating, pulsed or random currents are delivered to the human head via scalp or earlobe electrodes. This approach is widely used in basic and translational studies. However, the underlying mechanisms of NCCS, which lead to biological and behavioral effects in the brain, remain largely unknown. In this review, we characterize NCCS techniques currently being utilized in neuroscience investigations, including transcranial alternating current stimulation (tACS), transcranial pulsed current stimulation (tPCS), transcranial random noise stimulation (tRNS), and cranial electrotherapy stimulation (CES). Method: We unsystematically searched all relevant conference papers, journal articles, chapters, and textbooks on the biological mechanisms of NCCS techniques. Results: The fundamental idea of NCCS is that these low-level currents can interact with neuronal activity, modulate neuroplasticity and entrain cortical networks, thus, modifying cognition and behavior. We elucidate the mechanisms of action for each NCCS technique. These techniques may cause microscopic effects (such as affecting ion channels and neurotransmission systems) and macroscopic effects (such as affecting brain oscillations and functional connectivity) on the brain through different mechanisms of action (such as neural entrainment and stochastic resonance). Conclusion: The appeal of NCCS is its potential to modulate neuroplasticity noninvasively, along with the ease of use and good tolerability. Promising and interesting evidence has been reported for the capacity of NCCS to affect neural circuits and the behaviors under their control. Today, the challenge is to utilize this advancement optimally. Continuing methodological advancements with NCCS approaches will enable researchers to better understand how NCCS can be utilized for the modulation of nervous system activity and subsequent behaviors, with possible applications to non-clinical and clinical practices.

Organic Changes in the Brain, Sleep Loss, and Sleep Modulation With Aging: A Review

Article

Full-text available

Jan 2023

The sleep loss (SL) are one of the important diseases that endanger the health of aging individuals. This study evaluated SL in aging individuals, and explored the relationship between age and the organic changes that affect brain and sleep. The causes of SL in aging individuals and its harmful effects on them have been outlined. To enable individuals in choosing a suitable way to sleep better, we also reviewed advantages and disadvantages of the existing sleep modulation based on lifestyle habits and drug and physical stimulation. We found the former as more suitable for patients with mild SL, while the latter may fail to achieve the desired effects and may even lead to the onset of new diseases. Therefore, it is proposed to use non-invasive electrical and magnetic stimulations to improve the sleep quality in aging patients.In this review, mechanisms of the two stimulation methods have been summarized. Through analysis, it was found that magnetic stimulation can induce neuronal action potential, which makes patients twitch, and equipment noise causes discomfort in the elderly during treatment. Comparative analysis of stimulation methods revealed that transcranial electrical stimulation (tES) is a considerably safe, convenient, non-invasive, and easy to operate method with few adverse reactions, and it can be considered a potential therapeutic method for SL in aging patients.

Axon morphology and intrinsic cellular properties determine repetitive transcranial magnetic stimulation threshold for plasticity

Preprint

Sep 2023

Repetitive transcranial magnetic stimulation (rTMS) is a widely used therapeutic tool in neurology and psychiatry, but its cellular and molecular mechanisms are not fully understood. Standardizing stimulus parameters, specifically electric field strength and direction, is crucial in experimental and clinical settings. It enables meaningful comparisons across studies and facilitating the translation of findings into clinical practice. However, the impact of biophysical properties inherent to the stimulated neurons and networks on the outcome of rTMS protocols remains not well understood. Consequently, achieving standardization of biological effects across different brain regions and subjects poses a significant challenge. This study compared the effects of 10 Hz repetitive magnetic stimulation (rMS) in entorhino-hippocampal tissue cultures from mice and rats, providing insights into the impact of the same stimulation protocol on similar neuronal networks under standardized conditions. We observed the previously described plastic changes in excitatory and inhibitory synaptic strength of CA1 pyramidal neurons in both mouse and rat tissue cultures, but a higher stimulation intensity was required for the induction of rMS-induced synaptic plasticity in rat tissue cultures. Through systematic comparison of neuronal structural and functional properties and computational modeling, we found that morphological parameters of CA1 pyramidal neurons alone are insufficient to explain the observed differences between the groups. However, axon morphologies of individual cells played a significant role in determining activation thresholds. Notably, differences in intrinsic cellular properties were sufficient to account for the 10 % higher intensity required for the induction of synaptic plasticity in the rat tissue cultures. These findings demonstrate the critical importance of axon morphology and intrinsic cellular properties in predicting the plasticity effects of rTMS, carrying valuable implications for the development of computer models aimed at predicting and standardizing the biological effects of rTMS.

Frontopolar multifocal transcranial direct current stimulation reduces conditioned fear reactivity during extinction training: A pilot randomized controlled trial

Article

Sep 2023
NEUROBIOL LEARN MEM

Targeted and optimized multi-channel transcranial direct current stimulation for focal epilepsy: An N-of-1 trial

Preprint

Full-text available

Sep 2023

Transcranial direct current stimulation (tDCS) has been used to noninvasively reduce epileptic activity in focal epilepsy. In this proof-of-principle N-of-1 trial in a patient with drug-resistant focal epilepsy, we propose distributed constrained maximum intensity (D-CMI) for individually targeted and optimized multi-channel (mc-)tDCS to reduce epileptic activity. Combined electro- and magnetoencephalography (EMEG) source analysis in a realistic calibrated head model defines location and orientation of the target epileptogenic source. Converging evidence for this determination is achieved by retrospective identification of a cortical malformation in magnetic resonance imaging and by successful EMEG-guided invasive EEG. We applied D-CMI in a double-blind, sham-controlled stimulation experiment. In two stimulation weeks, either D-CMI or sham stimulation with 4 mA injection current were applied twice every week-day for 20 min each, with a 20 min pause in between. EEG was recorded 1 h before and after stimulation. For D-CMI, we find a highly significant reduction in IED frequency (p < 0.0001) marked by three experts of on average 37% to 81% over the five days of stimulation (mean +- SD: 58% +- 19%), while this is not the case for sham. The proposed procedure was well-tolerated and parameterizes a group clinical trial (Study registration number: DRKS00029384).

Modulating P-glycoprotein Regulation as a Therapeutic Strategy for Pharmacoresistant Epilepsy

Chapter

Aug 2023

Experimental data suggest a role of blood–brain barrier P-glycoprotein overexpression as a factor contributing to drug-resistant epilepsy. Therefore, efforts are made to develop and validate therapeutic approaches that aim to overcome transporter-mediated drug resistance. Considering the physiological function of efflux transporters, it will be advantageous to preserve the basal transport function. Thus, recent studies focused on the elucidation of key signaling factors driving P-glycoprotein upregulation in response to epileptic seizure activity. Based on these investigations, novel concepts have been developed: blocking the signaling pathway and controlling P-glycoprotein expression despite recurrent seizure activity. Further development of respective approaches is based on ongoing studies that explore the relevance of the signaling mechanisms in human capillaries and preclinical animal models. In general, the success of respective strategies will depend on the question of whether patients exist in which P-glycoprotein overexpression constitutes a predominant factor contributing to therapeutic failure.KeywordsP-glycoproteinEfflux transportersGlutamateCyclooxygenase-2Drug-resistant Epilepsy

Realistic vOlumetric-Approach to Simulate Transcranial Electric Stimulation – ROAST – a fully automated open-source pipeline

Preprint

Full-text available

Apr 2019

Research in the area of transcranial electrical stimulation (TES) often relies on computational models of current flow in the brain. Models are built on magnetic resonance images (MRI) of the human head to capture detailed individual anatomy. To simulate current flow, MRIs have to be segmented, virtual electrodes have to be placed on these anatomical models, the volume is tessellated into a mesh, and the finite element model is solved numerically to estimate the current flow. Various software tools are available for each step, as well as processing pipelines that connect these tools for automated or semi-automated processing. The goal of the present tool -- ROAST -- is to provide an end-to-end pipeline that can automatically process individual heads with realistic volumetric anatomy leveraging open-source software (SPM8, iso2mesh and getDP) and custom scripts to improve segmentation and execute electrode placement. When we compare the results on a standard head with other major commercial software tools for finite element modeling (ScanIP, Abaqus), ROAST only leads to a small difference of 9% in the estimated electric field in the brain. We obtain a larger difference of 47% when comparing results with SimNIBS, an automated pipeline that is based on surface segmentation of the head. We release ROAST as a fully automated pipeline available online as a open-source tool for TES modeling.

Multitarget transcranial direct current stimulation for freezing of gait in Parkinson's disease

Article

Full-text available

Feb 2018
MOVEMENT DISORD

Background: Recent findings suggest that transcranial direct current stimulation of the primary motor cortex may ameliorate freezing of gait. However, the effects of multitarget simultaneous stimulation of motor and cognitive networks are mostly unknown. The objective of this study was to evaluate the effects of multitarget transcranial direct current stimulation of the primary motor cortex and left dorsolateral prefrontal cortex on freezing of gait and related outcomes. Methods: Twenty patients with Parkinson's disease and freezing of gait received 20 minutes of transcranial direct current stimulation on 3 separate visits. Transcranial direct current stimulation targeted the primary motor cortex and left dorsolateral prefrontal cortex simultaneously, primary motor cortex only, or sham stimulation (order randomized and double-blinded assessments). Participants completed a freezing of gait-provoking test, the Timed Up and Go, and the Stroop test before and after each transcranial direct current stimulation session. Results: Performance on the freezing of gait-provoking test (P = 0.010), Timed Up and Go (P = 0.006), and the Stroop test (P = 0.016) improved after simultaneous stimulation of the primary motor cortex and left dorsolateral prefrontal cortex, but not after primary motor cortex only or sham stimulation. Conclusions: Transcranial direct current stimulation designed to simultaneously target motor and cognitive regions apparently induces immediate aftereffects in the brain that translate into reduced freezing of gait and improvements in executive function and mobility. © 2018 International Parkinson and Movement Disorder Society.

Direct effects of transcranial electric stimulation on brain circuits in rats and humans

Article

Full-text available

Feb 2018

Transcranial electric stimulation is a non-invasive tool that can influence brain activity; however, the parameters necessary to affect local circuits in vivo remain to be explored. Here, we report that in rodents and human cadaver brains, ~75% of scalp-applied currents are attenuated by soft tissue and skull. Using intracellular and extracellular recordings in rats, we find that at least 1 mV/mm voltage gradient is necessary to affect neuronal spiking and subthreshold currents. We designed an 'intersectional short pulse' stimulation method to inject sufficiently high current intensities into the brain, while keeping the charge density and sensation on the scalp surface relatively low. We verify the regional specificity of this novel method in rodents; in humans, we demonstrate how it affects the amplitude of simultaneously recorded EEG alpha waves. Our combined results establish that neuronal circuits are instantaneously affected by intensity currents that are higher than those used in conventional protocols.

Low frequency transcranial electrical stimulation does not entrain sleep rhythms measured by human intracranial recordings

Article

Full-text available

Oct 2017

Transcranial electrical stimulation has widespread clinical and research applications, yet its effect on ongoing neural activity in humans is not well established. Previous reports argue that transcranial alternating current stimulation (tACS) can entrain and enhance neural rhythms related to memory, but the evidence from non-invasive recordings has remained inconclusive. Here, we measure endogenous spindle and theta activity intracranially in humans during low-frequency tACS and find no stable entrainment of spindle power during non-REM sleep, nor of theta power during resting wakefulness. As positive controls, we find robust entrainment of spindle activity to endogenous slow-wave activity in 66% of electrodes as well as entrainment to rhythmic noise-burst acoustic stimulation in 14% of electrodes. We conclude that low-frequency tACS at common stimulation intensities neither acutely modulates spindle activity during sleep nor theta activity during waking rest, likely because of the attenuated electrical fields reaching the cortical surface.

Physiology of Transcranial Direct Current Stimulation

Article

Jun 2018

Direct current stimulation is a neuromodulatory noninvasive brain stimulation tool, which was first introduced in animal and human experiments in the 1950s, and added to the standard arsenal of methods to alter brain physiology as well as psychological, motor, and behavioral processes and clinical symptoms in neurological and psychiatric diseases about 20 years ago. In contrast to other noninvasive brain stimulation tools, such as transcranial magnetic stimulation, it does not directly induce cerebral activity, but rather alters spontaneous brain activity and excitability by subthreshold modulation of neuronal membranes. Beyond acute effects on brain functions, specific protocols are suited to induce long-lasting alterations of cortical excitability and activity, which share features with long-term potentiation and depression. These neuroplastic processes are important foundations for various cognitive functions such as learning and memory formation and are pathologically altered in numerous neurological and psychiatric diseases. This explains the increasing interest to investigate transcranial direct current stimulation (tDCS) as a therapeutic tool. However, for tDCS to be used effectively, it is crucial to be informed about physiological mechanisms of action. These have been increasingly elucidated during the last years. This review gives an overview of the current knowledge available regarding physiological mechanisms of tDCS, spanning from acute regional effects, over neuroplastic effects to its impact on cerebral networks. Although knowledge about the physiological effects of tDCS is still not complete, this might help to guide applications on a scientifically sound foundation.

Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo

Article

Mar 2018
BRAIN STIMUL

Background: Transcranial direct current stimulation (tDCS) is a promising brain modulation technique for several disease conditions. With this technique, some portion of the current penetrates through the scalp to the cortex and modulates cortical excitability, but a recent human cadaver study questions the amount. This insufficient intracerebral penetration of currents may partially explain the inconsistent and mixed results in tDCS studies to date. Experimental validation of a transcranial alternating current stimulation-generated electric field (EF) in vivo has been performed on the cortical (using electrocorticography, ECoG, electrodes), subcortical (using stereo electroencephalography, SEEG, electrodes) and deeper thalamic/subthalamic levels (using DBS electrodes). However, tDCS-generated EF measurements have never been attempted. Objective: We aimed to demonstrate that tDCS generates biologically relevant EF as deep as the subthalamic level in vivo. Methods: Patients with movement disorders who have implanted deep brain stimulation (DBS) electrodes serve as a natural experimental model for thalamic/subthalamic recordings of tDCS-generated EF. We measured voltage changes from DBS electrodes and body resistance from tDCS electrodes in three subjects while applying direct current to the scalp at 2 mA and 4 mA over two tDCS montages. Results: Voltage changes at the level of deep nuclei changed proportionally with the level of applied current and varied with different tDCS montages. Conclusions: Our findings suggest that scalp-applied tDCS generates biologically relevant EF. Incorporation of these experimental results may improve finite element analysis (FEA)-based models.

New waves: Rhythmic electrical field stimulation systematically alters spontaneous slow dynamics across mouse neocortex

Article

Mar 2018
NEUROIMAGE

Automatic skull segmentation from MR images for realistic volume conductor models of the head: Assessment of the state-of-the-art

Article

Mar 2018
NEUROIMAGE

Anatomically realistic volume conductor models of the human head are important for accurate forward modeling of the electric field during transcranial brain stimulation (TBS), electro- (EEG) and magnetoencephalography (MEG). In particular, the skull compartment exerts a strong influence on the field distribution due to its low conductivity, suggesting the need to represent its geometry accurately. However, automatic skull reconstruction from structural magnetic resonance (MR) images is difficult, as compact bone has a very low signal in magnetic resonance imaging (MRI). Here, we evaluate three methods for skull segmentation, namely FSL BET2, the unified segmentation routine of SPM12 with extended spatial tissue priors, and the skullfinder tool of BrainSuite. To our knowledge, this study is the first to rigorously assess the accuracy of these state-of-the-art tools by comparison with CT-based skull segmentations on a group of ten subjects. We demonstrate several key factors that improve the segmentation quality, including the use of multi-contrast MRI data, the optimization of the MR sequences and the adaptation of the parameters of the segmentation methods. We conclude that FSL and SPM12 achieve better skull segmentations than BrainSuite. The former methods obtain reasonable results for the upper part of the skull when a combination of T1- and T2-weighted images is used as input. The SPM12-based results can be improved slightly further by means of simple morphological operations to fix local defects. In contrast to FSL BET2, the SPM12-based segmentation with extended spatial tissue priors and the BrainSuite-based segmentation provide coarse reconstructions of the vertebrae, enabling the construction of volume conductor models that include the neck. We exemplarily demonstrate that the extended models enable a more accurate estimation of the electric field distribution during transcranial direct current stimulation (tDCS) for montages that involve extraencephalic electrodes. The methods provided by FSL and SPM12 are integrated into pipelines for the automatic generation of realistic head models based on tetrahedral meshes, which are distributed as part of the open-source software package SimNIBS for field calculations for transcranial brain stimulation.

Studying and modifying brain function with non-invasive brain stimulation

Article

Jan 2018

In the past three decades, our understanding of brain-behavior relationships has been significantly shaped by research using non-invasive brain stimulation (NIBS) techniques. These methods allow non-invasive and safe modulation of neural processes in the healthy brain, enabling researchers to directly study how experimentally altered neural activity causally affects behavior. This unique property of NIBS methods has, on the one hand, led to groundbreaking findings on the brain basis of various aspects of behavior and has raised interest in possible clinical and practical applications of these methods. On the other hand, it has also triggered increasingly critical debates about the properties and possible limitations of these methods. In this review, we discuss these issues, clarify the challenges associated with the use of currently available NIBS techniques for basic research and practical applications, and provide recommendations for studies using NIBS techniques to establish brain-behavior relationships.

Transcranial Direct Current Stimulation Facilitates Associative Learning and Alters Functional Connectivity in the Primate Brain

Article

Oct 2017
CURR BIOL

There has been growing interest in transcranial direct current stimulation (tDCS), a non-invasive technique purported to modulate neural activity via weak, externally applied electric fields. Although some promising preliminary data have been reported for applications ranging from stroke rehabilitation to cognitive enhancement, little is known about how tDCS affects the human brain, and some studies have concluded that it may have no effect at all. Here, we describe a macaque model of tDCS that allows us to simultaneously examine the effects of tDCS on brain activity and behavior. We find that applying tDCS to right prefrontal cortex improves monkeys' performance on an associative learning task. While firing rates do not change within the targeted area, tDCS does induce large low-frequency oscillations in the underlying tissue. These oscillations alter functional connectivity, both locally and between distant brain areas, and these long-range changes correlate with tDCS's effects on behavior. Together, these results are consistent with the idea that tDCS leads to widespread changes in brain activity and suggest that it may be a valuable method for cheaply and non-invasively altering functional connectivity in humans.

Immediate neurophysiological effects of transcranial electrical stimulation

Abstract

Supplementary resource (1)

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Supplementary Material

Cutaneous Sensation of Electrical Stimulation Waveforms

Analyzing EEG and MEG signals recorded during tES, a reply