memory and cognition-related neuroplasticity enhancement...
TRANSCRIPT
Review ArticleMemory and Cognition-Related NeuroplasticityEnhancement by Transcranial Direct Current Stimulation inRodents: A Systematic Review
Carla Cavaleiro,1,2,3 João Martins,1,2,3,4 Joana Gonçalves ,1,2
and Miguel Castelo-Branco 1,2,3,4
1Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Coimbra, Portugal2Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal3CNC.IBILI Consortium, University of Coimbra, Coimbra, Portugal4Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Correspondence should be addressed to Joana Gonçalves; [email protected] Miguel Castelo-Branco; [email protected]
Received 6 December 2019; Revised 27 January 2020; Accepted 6 February 2020; Published 26 February 2020
Guest Editor: Luca Marsili
Copyright © 2020 Carla Cavaleiro et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Brain stimulation techniques, including transcranial direct current stimulation (tDCS), were identified as promising therapeutictools to modulate synaptic plasticity abnormalities and minimize memory and learning deficits in many neuropsychiatricdiseases. Here, we revised the effect of tDCS on the modulation of neuroplasticity and cognition in several animal diseasemodels of brain diseases affecting plasticity and cognition. Studies included in this review were searched following the terms(“transcranial direct current stimulation”) AND (mice OR mouse OR animal) and according to the PRISMA statementrequirements. Overall, the studies collected suggest that tDCS was able to modulate brain plasticity due to synaptic modificationswithin the stimulated area. Changes in plasticity-related mechanisms were achieved through induction of long-term potentiation(LTP) and upregulation of neuroplasticity-related proteins, such as c-fos, brain-derived neurotrophic factor (BDNF), or N-methyl-D-aspartate receptors (NMDARs). Taken into account all revised studies, tDCS is a safe, easy, and noninvasive brain stimulationtechnique, therapeutically reliable, and with promising potential to promote cognitive enhancement and neuroplasticity. Sincethe use of tDCS has increased as a novel therapeutic approach in humans, animal studies are important to better understand itsmechanisms as well as to help improve the stimulation protocols and their potential role in different neuropathologies.
1. Introduction
Transcranial direct current stimulation (tDCS) is a noninva-sive brain stimulation technique that promotes transientpolarity-dependent changes in spontaneous neuronal activ-ity. This effect is mediated by the application of constantlow-amplitude electrical currents using epicranially posi-tioned electrodes above a specific brain region of interest[1–4]. The therapeutic use of low-amplitude electrical cur-rents has a long historical track. Accordingly, both Greeksand Romans used electric torpedo fishes for migraine treat-ment, and in the 11th century, a similar therapeutic proce-dure was attempted to handle epilepsy [5]. In the 19th
century, the application of galvanic currents was attemptedto heal melancholia [6]. Over the years, the scientific commu-nity interest in brain stimulation grew, and several noninva-sive brain stimulation techniques were developed such astDCS, deep brain stimulation, or transcranial magnetic stim-ulation. The epicranial application of direct currents pro-motes a weak electric field force and produces neuronalmembrane potential changes [7, 8]. These alterations occurthrough sodium and calcium currents [1] modulating spon-taneous neuronal activity [2]. The consequent regional neu-ronal inhibition or excitation depends on the applied currentpolarity [9, 10]. So, it was overall observed that cathodal cur-rents produce inhibitory effects, and thus hyperpolarization,
HindawiNeural PlasticityVolume 2020, Article ID 4795267, 23 pageshttps://doi.org/10.1155/2020/4795267
whereas anodal currents increase excitability in the form ofdepolarization [2, 11] (Figure 1).
There is nowadays an ongoing discussion regarding thefactors that interfere with tDCS outcomes. The initial brainresting state of each subject [12], his/her baseline perfor-mance [13], specific individual variations in brain tissuemorphology [14], or even more particular details from theexperimental design or stimulation protocol used [15]influence these outcomes. In vivo and in vitro studies areconsensual to demonstrate that tDCS-modulated corticalexcitability depends on several stimulation parameters, suchas duration and frequency of stimulation [16]; polarity,intensity, and density of the applied current [17, 18]; andelectrode size and position in the scalp [18–20]. Despite that,beneficial effects of tDCS in several brain disorders, such asPD [21, 22], depression [23], stroke [24, 25], or autism [26,27], have been documented, and there is growing evidenceproposing tDCS application in multiple other disease condi-tions affecting cognition and neuroplasticity mechanisms.
Both preclinical and clinical studies have demonstratedtherapeutic effects of tDCS. Indeed, in human studies, anodaltDCS applied intermittently in the prefrontal cortex (PFC)during slow-wave sleep period, improved recall of declarativememories (word pairs). The authors correlated these findingswith enhancement of slow oscillatory electroencephalogram(EEG) activity (<3Hz, delta (δ) waves), responsible forneuronal plasticity facilitation [28]. Also, anodal tDCS overdorsolateral prefrontal cortex (DLPFC) improved workingmemory in PD patients and in major depression patients byboosting cortical excitability [21, 23]. Accordingly, preclini-cal animal studies reported that cortical anodal tDCSimproved spatial memory in both wild type (WT) [29] andthe AD rat model [30]. Beneficial effects were also found dur-ing the early stage of traumatic brain injury (TBI) [31] andfollowing a pilocarpine-induced status epilepticus in normalrats [32]. Moreover, improvements were also reported con-cerning short-term memory in an animal model of attentiondeficit hyperactivity disorder (ADHD) [33].
The molecular mechanisms underlying the tDCS-mediated cognitive improvements and neuroplasticity pro-cesses have become the focus of recent interest. Accordingly,tDCS modulation over several cognition-related plasticitygenes and their signaling pathways has been studied. In thisreview, we provide a state of the art on the application ofdifferent protocols of tDCS in animal models highlightingits effectiveness on neuroplasticity mechanisms and, conse-quently, their related learning and memory processes. Sincethe published systematic reviews focused on human applica-tion of tDCS, here, we provide a comprehensive revision ofthe effect of tDCS in in vivo rodent models of normal andpathological brain functioning.
2. Methods
2.1. Data Sources and Search. Studies included in this reviewwere identified by searching PubMed. The search was rununtil 31 October 2019. The search terms were (“transcranialdirect current stimulation”) AND (mice OR mouse OR ani-mal). Articles were firstly assessed based on their abstracts
and titles, aiming to include studies that reported applyingtDCS to cognitive impairment in animal models. Simulta-neously, the following exclusion criteria were adopted toreject studies: (1) not written in English; (2) performingreviews; (3) in human subjects; (4) in vitro models; (5)employing other brain stimulation techniques (e.g., transcra-nial magnetic stimulation (TMS), deep brain stimulation(DBS), or transcranial alternating current stimulation(tACS)); and (6) not explicitly describing the tDCS protocol(stimulation area, number of sessions, frequency, intensity,and pattern).
2.2. Data Extraction. A data extraction sheet was developedseeking to retrieve relevant information from each study,namely, study design, sample size, animal model, whetheradditional therapy was performed, details of the tDCS proto-col, outcome measures, and behavioral results.
2.3. Study Selection. The database search was elaboratedaccording to the PRISMA statement requirements [34]. 404records were found, which underwent a preliminary screen-ing (of titles and abstracts), with 314 records being excludedbecause they did not meet the eligibility criteria. After thefull-text analysis of each of the 90 individual articles, 44rodent studies focusing on tDCS effects over cognition andneuroplasticity in both healthy and neuropathological animalmodels were selected (Figure 2).
3. Results
3.1. Role of Anodal tDCS in Cognition Processing in HealthyAnimals. In healthy animals, studies demonstrated memoryimprovement in association with induction of synapticplasticity mechanisms. In fact, tDCS to prefrontal corteximproved monkey’s performance on an associative learningtask by altering low-frequency oscillations and functionalconnectivity, both locally and between distant brain areas[35]. Regarding rodent models, data are controversial regard-ing fear condition. Right frontal anodal tDCS administered24 h before behavioral task did not alter contextual and audi-tory learning and memory [36]. Additionally, another studydescribed that while the anodal stimulation did not affect fearretrieval, posttraining cathodal stimulation improved fearmemory retrieval [37, 38]. However, left prefrontal anodaland cathodal tDCS impaired the acquisition of both contex-tual and cued fear memory, which could be explained byactivity modulation of deep structures such as the amygdalaand hippocampus [39].
Concerning learning and memory, de Souza Custódioand colleagues [29] reported better spatial working memoryperformance following administration of anodal currents tothe medial prefrontal cortex (mPFC). In agreement, it wasdescribed that administration of hippocampal anodal tDCSimproves learning and memory in the Morris water mazeand novel object recognition tests [40]. Moreover, memoryperformance in the passive avoidance learning task wasenhanced by anodal stimulation [41]. Also, cortical cathodalstimulation together with visuospatial memory training ledto cognitive improvement [42].
2 Neural Plasticity
The revised in vivo animal model studies regarding tDCSeffects in memory and cognition of healthy animals are listedbelow in Table 1.
3.2. Beneficial Role of tDCS in Brain Diseases.Overall, reportsusing animal models of brain diseases described a beneficialrole of tDCS in the mitigation of memory symptoms of neu-rologic conditions such as Alzheimer’s disease (AD) or trau-matic brain injury (TBI). More recent studies demonstrated
that tDCS rescued AD-related cognitive symptoms, namely,spatial memory and motor skills [30, 43, 44]. The repetitivestimulation with anodal tDCS in the AD-like dementia ratmodel reduced the time interval animals needed to reacha food pellet and also decreased the number of errors inthe attempt [43]. The same research group showed laterthat the abovementioned protocol rescued spatial learningand memory in a Aβ1-40-lesioned AD rat model [30].Moreover, the impact of tDCS on cognitive performance
Electric currentinto the brain
Electric currentinto the brain
Referenceelectrode
Activeelectrode
Direct currentstimulator
Anodal stimulation
Depolarized soma
Excitation
Cathodal stimulation
Hyperpolarized soma
Inhibition
−
+
−
+
Figure 1: Illustration of transcranial direct current stimulation in the mice. Anodal stimulation depolarizes the neuronal membrane andenhances excitability. On the other hand, cathodal stimulation hyperpolarizes the neuronal membrane and decreases excitability.
# of records identified throughPubmed database searching: 404
# of records screened: 404
# of full-text articlesassessed for eligibility: 90
# of rodent studies includedin the qualitative synthesis: 44
# of records excluded: 314220 reviews and methods(i)
(ii)(iii)(iv)
8 in vitro studies36 human studies50 studies regarding otherbrain stimulation techniques(e.g., TMS, DB and tACS)
Figure 2: Search flow diagram (in accordance with PRISMA statement). Abbreviations: DB: deep brain stimulation; tACS: transcranialalternating current stimulation; TMS: transcranial magnetic stimulation.
3Neural Plasticity
Table1:Effectof
transcranialdirectcurrentstim
ulationon
mem
oryandlearning
ofhealthyanim
als.
Autho
rYear
Animal
mod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(m2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Dockery
etal.[42]
2011
NDM
Long-
Evans
rats;
males
41a-tD
CS
vs.
c-tD
CS
Fron
talcortex
(leftor
right
hemisph
ere)
0.2
0.035
3057.1
Back
10.5
NY(3
days)
↑Visuo
spatialw
orking
mem
ory(c-tDCS)
deSouza
Custódio
etal.[29]
2013
NDM
Wistar
rats;m
ales
23a-tD
CS
LeftmPFC
0.4
0.25
11N/A
Neck
1N
Y(5
days)
↑Spatialw
orking
mem
ory
(1h,
4h,
and10
hpo
ststim
ulation)
Faraji
etal.[96]
2013
NDM
Long-
Evans
rats;
males
24a-tD
CS
Somatosensory
cortex
(bilateral)
0.065
N/A
10N/A
Backof
skull
N/A
NY
↑Corticaln
eurald
ensity
↑Motor
learning
(a-tDCSappliedbilaterally
orinto
pawpreferredto
reaching
contralateral
hemisph
ere)
Pod
daetal.[40]
2016
NDM
C57BL/6
mice;
males
16a-tD
CS
vs.
c-tD
CS
Leftparietal
cortex
(dorsalto
hipp
ocam
pal
form
ation)
0.35
0.06
20N/A
Ventral
thorax
5.2
NN
(single
session)
↑Spatiallearningand
mem
ory
(a-tDCS;benefits
observableon
eweekafter)
↑BDNFexpression
sin
the
hippocam
pus
CREB/CBPpathway
activation
Manteghi
etal.[36]
2017
NDM
NMRI
mice;
males
64a-tD
CS
Right
fron
tal
cortex
0.2
0.04
20N/A
Chest
9.5
N/A
N(single
session)
↓Freezing
time%
and↑
latencyto
thefreezing
(tDCSfollowing0.1mg/kg
ACPAinjection)
Nasehi
etal.[37]
2017
NDM
NMRI
mice;
males
128
a-tD
CS
vs.
c-tD
CS
Right
fron
tal
cortex
0.2
0.04
20N/A
Ventral
thorax
9.5
NY(2
sessions)
↑Fear
mem
ory
retrieval/freezing
time
(a-tDCSandprop
rano
lol
injectionbefore
cond
itioning)
Nasehi
etal.[38]
2017
NDM
NMRI
mice;
males
128
a-tD
CS
vs.
c-tD
CS
Leftfron
tal
cortex
0.2
0.04
20N/A
Ventral
thorax
9.5
NY(2
sessions)
↑Con
textualfearmem
ory
acqu
isition
(a-tDCSbefore
pre-
orpo
sttraining)
Abbasi
etal.[39]
2017
NDM
NMRI
mice;
males
41a-tD
CS
vs.
c-tD
CS
LeftPFC
0.2
0.04
20or
30N/A
Chest
9.5
NN
(single
session)
↓Con
textualand
cued
fear
mem
ory
4 Neural Plasticity
Table1:Con
tinu
ed.
Autho
rYear
Animal
mod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(m2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Martins
etal.[97]
2019
NDM
Male
Wistar
rats;m
ales
50a-tD
CS
LeftmPFC
0.4
N/A
13N/A
N/A
N/A
N/A
Y(5
days)
↑Spatialw
orking
mem
ory
↑GAP-43(extinctby
AMPARantagonistPRP)
Yuetal.
[41]
2019
NDM
Sprague
Daw
ley
rats;m
ales
224
a-tD
CS
SCdo
rsalto
the
hippocam
pus
0.25
0.25
30N/A
Anterior
chest
N/A
(EEG
electrod
e)Y
N(single
session)
↑Mem
ory
(passive
avoidance
mem
oryretention)
↑LT
Pin
CA1hippocam
pus
(blocked
byTrkB
antagonist)
↑BDNFin
CA1
hippocam
pus
Abbreviations:rtD
CS:repetitive
transcranialdirectcurrentstimulation;a-tD
CS:anod
altranscranialdirectcurrentstimulation;c-tD
CS:cathod
altranscranialdirectcurrentstimulation;SC
:stereotaxiccoordinates;
C57BL/6:
mou
sestrain;N
MRI:Naval
Medical
ResearchInstituteou
tbredmice;NBM:n
odiseasemod
el;SHR:spo
ntaneous
hypertensive
rats;W
KY:W
istarKyoto
rats;P
FC:p
refron
talcortex;m
PFC
:medial
prefrontal
cortex;ITC:inferotempo
ralcortex;CAI:comuam
mon
is1region
inthehipp
ocam
pus;PRP:perampanel;ACPA:anticitrullin
ated
proteinantibody
(selective
cann
abinoidCBIreceptor
agon
ist);
AMPAR:α
-amino-3-hydroxy-5-methyl-4-isoxazolepropion
icacid
receptor;T
rk:tropo
myosinreceptor
kinase
receptor;C
REB/CBP:cAMPrespon
seelem
entbind
ingprotein;
BDNF:
brain-derivedneurotroph
icfactor;G
AP-43:
grow
th-associatedprotein43;L
TP:lon
g-term
potentiation
;EEG:electroenceph
alograph
y;A/m
2 :am
pere
persquare
meter;m
A:m
illiampere;cm
2 :square
centim
eter;m
m:m
illim
eter;h
:hou
r;min:m
inute;vs.:versus;Y
:yes;N
:no;N/A
:not
available.
5Neural Plasticity
of streptozotocin-induced diabetic rats has been evaluated.Both anodal and cathodal stimulations in the prefrontalcortex restored memory impairment [45, 46] together withrestoration of LTP [45]. Other authors evaluated the poten-tial therapeutic effects of tDCS in memory impairment inan animal model of ADHD. It was found that this neuro-modulation technique was able to improve short- andlong-term memory deficits in the spontaneous hypertensiverats (SHR) but not in their control, Wistar Kyoto rats [33,47]. In addition, no changes were detected in workingmemory of these control rats following administration oftDCS [47].
Anodal tDCS also ameliorated behavioral and spatialmemory function in the early phase after TBI when it wasdelivered two weeks postinjury. However, earlier stimulationonly improved spatial memory [31]. In a later phase of TBI, itwas possible to observe motor recovery as well as spatialmemory improvement following repeated anodal tDCS[48]. A growing number of studies has been reporting prom-ising effects of neurostimulation in models of addictive disor-ders, by reducing craving and maladaptive pervasive learning[49]. In fact, repeated anodal stimulation in mouse frontalcortex decreased nicotine-induced conditioned place prefer-ence and further improved working memory [50]. Samepolarity currents also could prevent cocaine-induced loco-motor hyperactivity and place preference conditioning [51].In addition, it has been reported that cathodal stimulationhas an anticonvulsive effect [16, 32, 52–54]. Indeed, theadministration of hippocampal tDCS rescued cognitiveimpairment by reducing hippocampal neural death andsupragranular and CA3 mossy fiber sprouting in a lithium-pilocarpine-induced status epilepticus rat [32]. Other neuro-plastic effects were evidenced in the reversion of motorsymptoms in PD by tDCS administration. The applicationof anodal currents enhanced graft survival and dopaminergicre-innervation of the surrounding striatal tissue and pro-nounced behavioral recovery [55].
Despite the fact that many studies reported recovery frommemory deficits following tDCS stimulation, there are someopposing reports in animal models of disease affecting cogni-tion. In a recent study from Gondard and collaborators usinga triple transgenic (3xTg) mouse model of AD, it was evi-denced that a neurostimulation was not able to amelioratememory symptoms [56]. To reconcile this discrepancy, pre-vious authors have suggested the importance of choosingan optimal current intensity in order to modulate corticalexcitability since LTP alterations were dependent on currentintensity [57].
The reports regarding tDCS effects in cognition andmemory in animal models of brain disease are listed inTables 2 and 3.
3.3. Effect of tDCS on Cellular and Molecular NeuroplasticityMechanisms. Neuronal network reorganization underliesneuroplasticity processes like developmental synaptogenesis,or neurogenesis and synaptic turnover later on, which ulti-mately contributes to optimal brain development and aging,as well as functional recovery upon trauma [58]. Interest-ingly, several reports using genetic engineered animals, phar-
macologically induced animal models of disease, or in vitrotechniques enlightened the potential of direct current stimu-lation (DCS) to interact with a myriad of neuroplasticity-related processes such as neuroinflammation [59, 60], neuralstem cell migration [59], neurite growth [61], or neurogen-esis [62]. Moreover, both human and in vivo animal studiesevidenced a tDCS-induced effect on memory and learning[28, 35, 63]. However, the underlying cellular and molecularmechanisms remain to be elucidated.
3.3.1. Modulation of the Excitatory/Inhibitory Network. Todate, animal experimental evidence highlighted tDCS influ-ences on synaptic plasticity, through alterations in thefunctional connectivity of cognition-related areas [35] andby modulation of excitatory/inhibitory network tonus[64], which may involve both the GABAergic and gluta-matergic systems. Accordingly, a study conducted witholder adults remarked an anodal stimulation effect ingamma-aminobutyric acid (GABA) levels [65]. Similarly, inhuman healthy volunteers, an anodal tDCS effect in motorlearning was correlated with a decrease in GABA levels, anoutcome known to be a determinant factor in the promotionof long-term potentiation- (LTP-) dependent plasticity andtherefore learning [66, 67].
Several preclinical studies probed LTP enhancement fol-lowing direct current stimulation. Anodal DCS enhancedLTP in both mouse cortex [68] and rat hippocampal slices[69, 70]. Further, this neurostimulation method increasedlocal field potential (LFPs) amplitudes in primary somato-sensory cortex of rabbits [63]. Also, other works demon-strated that neurostimulation-enhanced hippocampal LTPwas associated with better spatial memory performancealong with an increase in brain-derived neurotrophic factor(BDNF) expression levels [40]. An opposite effect on LTPand LFPs was obtained with administration of cathodal cur-rents. In agreement, a report from Sun et al. [71] evidencedthat cathodal currents applied in mouse neocortical slicesinduced field excitatory postsynaptic potential depression.This type of LTD was smothered by application of anmGluR5 negative allosteric modulator [72]. These findingssupport a possible modulatory effect of tDCS on mGluR5-mTOR signaling [72]; these molecular pathways are recog-nized to disturb cognition-related synaptic plasticity.
Further evidence supporting tDCS effect on LTP-likemechanisms was recently brought to light by Stafford et al.[73]. These authors observed that a single anodal tDCSincreased both the phosphorylation at the S831 of GluA1subunit and the translocation of α-amino-3-hydroxy5-methyl-4-isoxazole propionic acid receptors (AMPARs)from cytosolic to synaptic fractions in the hippocampus.These data could be favoring learning enhancement, as thistranslocation has been associated with hippocampal LTPinduction [72]. Accordingly, others reported a spatial work-ing memory enhancement after anodal stimulation over leftmedial PFC that was lost with the administration of theAMPAR antagonist perampanel (PRP). In contrast tocathodal currents, anodal currents enhanced intracellularcalcium (Ca2+) intake in cell cultures including astrocytes[74–76], a process associated with AMPAR phosphorylation
6 Neural Plasticity
Table2:Im
pactof
transcranialdirectcurrentstim
ulationon
mem
oryandlearning
inanim
almod
elsof
braindisorders.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Kam
ida
etal.[32]
2011
Lithium-
pilocarpine
hydrochloride
(60mg/kg)SC
injectionat
P20-21
Wistar
rats;m
ales
18c-tD
CS
Hippo
campu
s0.2
0.035
30N/A
Backof
neck
N/A
NY(dailyfor2
weeks)
↓SE
-ind
uced
hipp
ocam
palcellloss
inCA3region
Yuetal.
[43]
2014
Scop
olam
ine
IPinjection
Sprague
Daw
ley
rats;both
gend
ers
16N/A
Parietalcortex
(hippo
campu
s)0.1
N/A
20N/A
N/A
N/A
N/A
Y(2x/daydu
ring
5days
aweek,
for4weeks)
↓Tim
eand↓
numberof
errors
toreachfood
pellets
Significant
differencesin
ACh
content(day
14and
day28)
↑Motor
function
Pedron
etal.[49]
2014
NicotineIP
injection
(1mh/kg
2x/day
for14
days)
Swiss
mice;
females
152
a-tD
CS
Leftfron
tal
cortex
0.2
0.035
2×20
N/A
Ventral
thorax
9.5
NY(5
days)
↑Working
mem
ory
↑Nicotine-indu
ced
placepreference
cond
itioning
(3weeks
poststim
ulation)
Yuetal.
[30]
2015
Bilateral
hippocam
pus
Aβ1-40
injection
Sprague
Daw
ley
rats;
females
36a-tD
CS
Right
fron
tal
cortex
0.02;0.06;
0.1;0.2
0.0314
20N/A
Ventral
thorax
10N
Y(10sessions
in2weeks)
↑Spatiallearning
performance
(best
with0.1mAand
0.2mAstim
ulation)
↓GFA
Pexpression
inCA1hippocam
pus
region
andDG(best
with0.1mA
stim
ulation)
Yoon
etal.[31]
2016
Lateralfl
uid
percussion
metho
d
Sprague
Daw
ley
rats;m
ales
36a-tD
CS
Hippo
campu
s0.2
0.0225
2028.2
Chest
48(corset)
YY(dailyfor5
days)
↑Perilesion
alarea
BDNFexpression
(tDCS2weeks
post-TBI)
↑Cho
line/creatinine
ratios
(tDCS1week
post-TBI)
Motor
performance
recovery
(2weeks
oftD
CS)
7Neural Plasticity
Table2:Con
tinu
ed.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Leffa
etal.[33]
2016
SHR
SHRrats
andWKT
rats;m
ales
48a-tD
CS
Fron
talcortex
0.5
1.5
2033.4
Between
ears
1.5
NY(8
consecutive
days)
↑DAlevelsin
STRin
both
ratstrainsand
inthehipp
ocam
pus
followingtD
CS
treatm
entin
WKY
↑BDNFlevelsin
WKYrats
Short-term
mem
ory
improvem
ent
Wuetal.
[45]
2017
STZ-ind
uced
diabeticrats
Sprague
Daw
ley
rats;m
ales
130
a-tD
CS
dPFC
0.2
0.0314
30N/A
Anterior
chest
0.25
YY
↑Spatialw
orking
mem
oryandmPFC
LTPrestoring
Pedron
etal.[50]
2017
Cocaine
injections
Swiss
mice;
females
165
a-tD
CS
Leftfron
tal
cortex
0.2
0.035
2×20
N/A
Ventral
thorax
9.5
N
Y(5
days
stim
ulation,
twiceaday;5h
interstimulation
interval)
↓Cocaine-ind
uced
locomotor
activity
Nococaine-indu
ced
placepreference
(5mg/kg
and
25mg/kg)
↑Zif2
68basal
expression
underthe
electrod
earea,inthe
STRandcortex
Leffa
etal.[55]
2018
ADHD
SHRand
WKYrats;
males
30a-tD
CS
(bicephalic)
Fron
talcortex
(sup
raorbital
area)
0.5
1.5(ECG
electrod
e)20
33.3
Neck
1.5(ECG
electrod
e)N/A
Y(8
days)
↓Inflam
matory
cytokinesand
reversionof
long-
term
mem
orydeficits
inSH
Rrats
Bragina
etal.[47]
2018
CCI
Mice;N/A
40a-tD
CS
Parietal
somatosensory
cortex
0.1
N/A
15N/A
Ventral
thorax
N/A
N/A
Y(dailyfor4
days,over4
weeks
and3days
interval)
Motor
coordination
recovery
Spatialm
emoryand
learning
performance
improvem
ent
↑CBFbilaterally
(regionalarteriolar
dilatation
and
hypo
xiaredu
ction)
Roostaei
etal.[44]
2019
STZ-ind
uced
diabeticrats
Wistar
rats;m
ales
64a-tD
CSvs.
c-tD
CS
Leftfron
tal
cortex
0.2
3.5
20N/A
Ventral
thorax
9.5
NY(twiceaday
over
2days)
Restoration
ofST
Z-
indu
cedam
nesia
(bothpo
larities)
8 Neural Plasticity
Table2:Con
tinu
ed.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Gon
dard
etal.[55]
2019
Animalmod
elof
AD-triple
transgenic
(3xT
g)mice
Triple
transgenic
(3xT
g)mice;
males
27c-tD
CSand
a-tD
CS
Second
ary
motor
cortex
(m2)
(c-TDCS)
anddo
rsal
tempo
ral
hippocam
pus
(a-tDCS)
0.05
0.0325
20N/A
N/A
0.0325
N/A
Y(5
days/week
for3weeks)
Notreatm
enteffect
onmem
oryou
tcom
eor
AD
neurop
atho
logical
biom
arkers
Abbreviations:rtD
CS:repetitive
transcranialdirectcurrentstimulation;a-tD
CS:anod
altranscranialdirectcurrentstimulation;c-tD
CS:cathod
altranscranialdirectcurrentstimulation;TBI:traumaticbraininjury;
ADHD:attention
deficith
yperactivitydisorder;SHR:spo
ntaneous
hypertensive
rats;W
KY:W
istarKyoto
rats;C
BF:cerebralbloodflow
;PFC
:prefron
talcortex;mPFC
:medialprefron
talcortex;dP
FC:dorsolateral
prefrontalcortex;D
G:dentategyrus;ST
R:striatum;M
2:second
arymotor
cortex;ITC:inferotem
poralcortex;CA3:cornuam
mon
is3region
inthehippocam
pus,ST
Z:streptozotocin;AD:A
lzheim
er’sdisease;Aβ1-
40:am
yloidbeta
peptide1–40;ACh:
acetylcholine;BDNF:
brain-derivedneurotroph
icfactor;DA:do
pamine;GFA
Pglialfibrillaryacidic
protein;
Zif2
68:zinc
finger
transcriptionfactor
268;
LTP:long-term
potentiation
;IP:intraperiton
eal;SC
:subcutaneous;SE
:status
epilepticus;ECG:electrocardiograph
y;mg:
milligram;kg:kilogram
;A/m
2 :am
pere
persquare
meter;mA:milliampere;cm
2 :square
centim
eter;
mm:m
illim
eter;h
:hou
r;min:m
inute;vs.:versus;Y
:yes;N
:no;N/A
:not
available.
9Neural Plasticity
Table3:Roleof
transcranialdirectcurrentstim
ulationon
neurop
lasticitywithafocuson
anim
almod
elsof
neurotraum
a.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Nekhend
zyetal.[97]
2004
Inflam
matory
nociceptionmod
el
Sprague
Daw
ley
rats;m
ales
31c-tD
CS
Fron
talcortex
2.25
N/A
45N/A
Bim
astoid
N/A
YY(8
days)
↓Nociceptive
respon
se(effectslasted
upto
50min
poststim
ulation)
Taibetal.
[98]
2009
Left
hemicerebellectom
yWistar
rats;m
ales
9a-tD
CS
Right
orleft
motor
cortex
0.4
0.071
2056.3
Supraorbital
region
0.0064
N/A
Y↑Tcorticom
uscular
respon
seam
plitud
es
Kim
etal.
[99]
2010
MCAO
Sprague
Daw
ley
rats;both
gend
ers
61c-tD
CSvs.
a-tD
CS
Leftprim
ary
motor
cortex
(M1)
0.1
0.785
30N/A
Trunk
9Y
Y(2
weeks)
Neuroprotection
over
whitematterand
ischem
icsize
↓(a-tDCS)
↑Motor
function
Jiangetal.
[95]
2012
MCAO
Sprague
Daw
ley
rats;both
gend
ers
90a-tD
CSand
c-tD
CS
Motor
cortex
0.1
0.785
301.27
Trunk
9Y
Y(daily,for
3,7,or
14days
postlesion
)
↑Motor
function
(7and14
days
poststroke)
↑Dendriticspine
density
↓PX1expression
(7th
and14
hday
poststroke)
Yoonetal.
[56]
2012
MCAO
Sprague
Daw
ley
rats;m
ales
30a-tD
CS
Leftprim
ary
motor
cortex
(M1)
0.2
N/A
2028.2
Anterior
chest
48.0
Y
Y(5
days
stim
ulation1
weekvs.1
day
postischem
ia)
↑Motor
function
and
Barnesmaze
performance
(a-tDCS
applied1weekafter
ischem
icinjury)
↑MAP-2
andGAP-43
expression
arou
ndthe
perilesion
alarea
(a-tDCSapplied1
weekpo
stischem
icinjury)
Lasteetal.
[100]
2012
CFA
injection/chronic
inflam
mation
indu
ction
Wistar
rats;m
ales
18a-tD
CS
Parietal
cortex
0.5
1.5(ECG
electrod
e)20
33.4
Supraorbital
area
1.5(ECG
electrod
e)N
Y(8
days)
Significant
differences
inno
ciceptive
respon
se(immediately
afterand24
hpo
ststim
ulation)
Adachi
etal.[101]
2012
CRS
Wistar
rats;m
ales
48a-tD
CS
Parietal
cortex
0.5
1.5(ECG
electrod
e)20
3.3
Supraorbital
area
1.5(ECG
electrod
e)N
Y(8
days)
↓Nociceptive
respon
sein
chronicstress
cond
ition
↓TNFexpression
inthehippocam
pus
10 Neural Plasticity
Table3:Con
tinu
ed.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Peruzzotti-
Jametti
etal.[60]
2013
MCAO
C57BL/6
mice;
males
137
c-tD
CSvs.
a-tD
CS
Leftparietal
cortex
0.25
0.0144
4055
Ventral
thorax
5.2
N/A
N(single
session)
↑Infarctv
olum
eand↑
BBBleakage(a-tDCS
ipsilesion
alhemisph
ere)
CorticalG
luactivity
↓,function
al↑and
ischem
icdamage↓
(c-tDCSipsilesion
alhemisph
ere)
Notturno
etal.[102]
2014
MCAO
Sprague
Daw
ley
rats;both
gend
ers
53c-tD
CS
Leftmotor
cortex
0.2
0.07
120
28.6
Ventral
thorax
10.5
YN
(single
session)
Ischem
iavolume↓
Luetal.
[103]
2015
MPTPinjection
C57bl
mice;
males
36a-tD
CS
Leftfron
tal
cortex
0.2
0.035
1057
Between
shou
lders
9N/A
Y(dailyfor3
weeks)
↑Motor
coordination
(until21
days
poststim
ulation)
↑TH
andDA
expression
↓Oxidative
stress
Spezia
Adachi
etal.[104]
2015
Restraint
stress
mod
elWistar
rats;m
ales
78a-tD
CS
Parietal
cortex
(midlin
e)0.5
1.5(ECG
electrod
e)20
N/A
Supraorbital
area
1.5(ECG
electrod
e)N
Y(dailyfor8
days)
↓Stress-ind
uced
nociceptiverespon
se↑Painthreshold
↓BDNFlevels(spinal
cord
andbrainstem)in
unstressed
anim
als
Yoonetal.
[31]
2016
Lateralfl
uid
percussion
metho
d
Sprague
Daw
ley
rats;m
ales
36a-tD
CS
Hippo
campu
s0.2
0.0225
2028.2
Chest
48(corset)
YY(dailyfor5
days)
↑Perilesion
alarea
BDNFexpression
(tDCS2weeks
post-TBI)
↑Cho
line/creatinine
ratios
(tDCS1week
post-TBI)
Motor
performance
recovery
(2weeks
oftD
CS)
Leffaetal.
[33]
2016
SHR
SHRrats
andWKT
rats;m
ales
48a-tD
CS
Fron
talcortex
0.5
1.5
2033.4
Betweenears
1.5
NY(8
consecutive
days)
↑DAlevelsin
STRin
both
ratstrainsandin
thehipp
ocam
pus
followingtD
CS
treatm
entin
WKY
↑BDNFlevelsin
WKY
rats
11Neural Plasticity
Table3:Con
tinu
ed.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Liuetal.
[105]
2016
PTI
Sprague
Daw
ley
rats;N
/A58
c-tD
CS
Right
S1FL
2N/A
2020.37
Venter
N/A
N/A
N(single
session)
Ischem
iaexpansion
inhibition
(c-tDCS
immediately
postischem
iaindu
ction)
↓NeuN
expression
(c-tDCS+
PSS
grou
p)
Braun
etal.
[106]
2016
MCAO
Wistar
rats;m
ales
41c-tD
CSvs.
a-tD
CS
Leftprim
ary
motor
cortex
(M1)
0.5
0.035
15N/A
Ventral
thorax
N/A
Y
Y(10-day
stim
ulation;
5days
with
2-day
interval)
Gaitrecoveryatday16
poststroke
(both
polarities)
Faster
recovery
oflim
bstrength
(fully
recoveredstrength
atday10
andgaitat
day
14withc-tD
CS)
↑Microgliaand
neuroblastsin
lesion
ipsilateralcortex
Cioatoetal.
[107]
2016
Sciaticnerve
chronic
constriction
Wistar
rats;m
ales
84a-tD
CSand
c-tD
CS
Parietal
cortex
(bicephalic)
0.5
1.5(ECG
electrod
e)20
N/A
Supraorbital
area
1.5(ECG
electrod
e)N
Y(8
days)
Nociceptive
relieve
(for
upto
7days
poststim
ulation)
Reversion
ofTIL-1þ
levels(48hand7days
poststim
ulation)
Filhoetal.
[108]
2016
Partialsciaticnerve
compression
Wistar
rats;m
ales
144
a-tD
CS
Parietal
cortex
0.5
1.5(ECG
electrod
e)20
N/A
Supraorbital
area
1.5(ECG
electrod
e)N
Y(8
days)
↓BDNFexpression
(48hpo
ststim
ulation)
Reversion
ofbehavioralalteration
s(analgesicand
anxiolytic)associated
withneurop
athicpain
Moreira
etal.[109]
2016
Painand
menop
ause
(ovariectomised
anim
als)
Wistar
rats;
females
45C-tDCS
Parietal
cortex
0.5
1.5(ECG
electrod
e)20
N/A
Supraorbital
area
1.5(ECG
electrod
e)N
Y(8
days)
↓Hypothalamic
BDNFlevelsandT
serum
BDNFin
ovariectom
ised
anim
als
Dim
ovetal.
[87]
2016
N/A
Wistar
rats;m
ales
25c-tD
CS
Leftprim
ary
motor
cortex
(M1)
0.25
0.0227
15N/A
Ventral
thorax
N/A
NN
(single
session)
Bilateral↓
Egr-1
expression
inthePAG
SpinalENK
immun
oreactivity↓in
theDHSC
12 Neural Plasticity
a-
Table3:Con
tinu
ed.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Liuetal.
[110]
2017
PTI
Sprague
Daw
ley
rats;m
ales
58c-tD
CS
S1FL
2N/A
20N/A
3mm
lateral
tolambd
aN/A
N/A
N(single
session)
Preventionof
ischem
iainjury
expansion
during
hyperacute
phaseof
ischem
ia(c-tDCS+
PSS)
Kim
&Han
[111]
2017
Mod
ified
Tang’s
metho
d[128]
Sprague
Daw
ley
rats;N
/A31
a-tD
CS
Leftmotor
cortex
0.2
130
0.26
Ventral
thorax
9Y
N
Earlyrecovery
ofconsciou
snessand
MEPandSE
Pprolon
gedlatency
(tDCSappliedright
afterTBI)
↓AstroglialG
FAP
immun
oreactivity
Winkler
etal.[112]
2017
Striatal6-OHDA
injection
Sprague
Daw
ley
rats;
females
24a-tD
CSand
c-tD
CS
Leftmotor
cortex
N/A
0.16
208
Chest
3N
Y(dailyfor
14days)
Graftsurvival,striatal
dopaminergic
reinnervationand
motor
recovery
(a-tDCS)
deSouza
etal.[113]
2017
PSN
LSw
iss
mice;
males
N/A
a-tD
CSand
c-tD
CS
Parietal
cortex
(bicephalic)
0.5
N/A
(EEG
electrod
e)5;10;15;20
N/A
Supraorbital
area
N/A
(EEG
electrod
e)N
N(single
session)
Antiallodyniceffect
(seen4h
poststim
ulationof
15min
and20
min)
Leffaetal.
[46]
2018
ADHD
SHRand
WKYrats;
males
30a-tD
CS
(bicephalic)
Fron
talcortex
(sup
raorbital
area)
0.5
1.5(ECG
electrod
e)20
33.3
Neck
1.5(ECG
electrod
e)N/A
Y(8
days)
↓Inflam
matory
cytokinesand
reversionof
long-term
mem
orydeficitsin
SHRrats
Paciello
etal.[114]
2018
NIH
LWistar
rats;m
ales
124
a-tD
CS
Tem
poral
lobe
(aud
itory
cortex)
0.35
0.0625
2056
Ventral
thorax
12N
Y(2
days)
↑Dendriticspines
density(layer
2/3
pyramidalneuron
sof
theauditory
cortex)
↑BDNFand
synaptop
hysin
expression
inauditory
cortex
(24h
poststim
ulation)
Fregni
etal.
[115]
2018
N/A
Wistar
rats;m
ales
32N/A
N/A
(bicephalic)
N/A
N/A
20N/A
N/A
N/A
N/A
Y(8
days)
tDCSpriorto
stress
expo
sure
prevented
thermalhyperalgesia
13Neural Plasticity
Table3:Con
tinu
ed.
Autho
rYear
Animalmod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Leeetal.
[116]
2019
MPTPinjection
C57bl
mice;male
60a-tD
CS
Primary
motor
cortex
(M1)
N/A
N/A
30N/A
Between
shou
lders
N/A
N/A
Y(dailyfor5
days)
↑Motor
coordination
Rescueof
MTPT-
indu
cedmitocho
ndrial
dysfun
ction(Ç
ATP
andGDH
and$Drp1
levels)
Callaietal.
[117]
2019
CCI-IO
NWistar
rats,m
ales
151
a-tD
CS
Parietal
cortex
(bicephalic)
0.5
1.5(ECG
electrod
e)20
N/A
Supraorbital
area
1.5(ECG
electrod
e)N
Y(8
days)
↓Mechanical
hyperalgesia
↓TNF-aexpression
(7days
poststim
ulation)
↓IL-10(7
days
poststim
ulation)
↓LD
Hserum
levels
Scarabelot
etal.[118]
2019
CFA
injection/chronic
inflam
mation
indu
ction
Sprague
Daw
ley
rats;m
ales
104
a-tD
CS
Parietal
cortex
(bicephalic)
0.5
1.5(ECG
electrod
e)20
N/A
Supraorbital
area
1.5(ECG
electrod
e)N/A
Y(8
days)
↓Therm
aland
mechanical
hyperalgesia
↑IL-6
(inbrainstem
24hpo
ststim
ulation)
↓IL-10(7
days
poststim
ulation)
Normalizationof
BDNFlevels(24h
poststim
ulation)
Abbreviations:rtD
CS:repetitive
transcranialdirect
currentstim
ulation;
a-tD
CS:anod
altranscranialdirect
currentstim
ulation;
c-tD
CS:cathod
altranscranialdirect
currentstim
ulation;
C57BL/6:mou
sestrain;
SHR:spon
taneou
shypertensive
rats;WKY:WistarKyoto
rats;ADHD:attentiondeficithyperactivitydisorder;6-OHDA:6-hydroxydop
amine;
MPTP:1-methyl-4-ph
enyl-1,2,3,6-tetrahydrop
yridine;
TBI:
traumatic
braininjury;PTI:ph
otothrom
bicischem
ia;MCAO:middlecerebral
artery
occlusion;
PSS:periph
eral
sensorystim
ulation;
NIH
L:no
ise-indu
cedhearingloss;CC-ION:chronicconstriction
ofthe
infraorbital
nerve(painmod
el);PSN
L:partialsciaticnerveligation(painmod
el);CRS:
chronicrestraintstress
(painmod
el);CFA
:com
pleteFreund
’sadjuvant
(painmod
el);BBB:b
lood
–brain
barrier;S1FL
:forelim
bregion
oftheprim
arysomatosensory
cortex;M1:
prim
arymotor
area;P
AG:periaquedu
ctal
grey;D
HSC
:dorsalho
rnof
thespinal
cord;M
EP:m
otor-evokedpo
tentials;S
EP:som
atosensory
evoked
potentials;G
FAP:g
lialfibrillaryacidic
protein;
BDNF:
brain-derivedneurotroph
icfactor;Glu:g
lutamateNeuN:neuron
almarker;PX1:
pann
exin
1;TH:thyroxinehydroxylase;Egr-1:earlygrow
threspon
seprotein1;
TNF:
tumor
necrosisfactor;IL-1þ:interleuk
in1beta;IL-6:
interleukin6;
IL-10:
interleukin10;L
DH:lactate
dehydrogenaseenzyme;ATP:adeno
sine
tripho
sphate;G
DH:glutamatedehydrogenase;
Drp1:
dynamin-related
protein;
MAP-2:microtubu
leassociated
protein
2;GAP-43:
grow
thassociated
protein
43;ENK:earlyem
bryo
specificNK;DA:do
pamine;
ECG:electrocardiograph
y;EEG:
electroencephalogram
;A/m
2 :am
pere
persquare
meter;m
A:m
illiampere;cm
2 :square
centim
eter;m
in:m
inute;vs.:versus;Y
:yes;N
:no;N/A
:not
available.
14 Neural Plasticity
nd trafficking to postsynaptic density [77] and ultimately,allowing LTP facilitation, a cellular correlate of learningand memory.
3.3.2. Activation of Neuroplasticity-Associated GeneExpression. Neurostimulation could have long-lasting effectsin memory as data from different studies evidenced [40].Authors have been argued that tDCS cognition modulationis associated with neuroplasticity-associated gene expressionalterations [78]. One of the neuroplasticity-associated genes,known to be essential for hippocampal LTP, is BDNF [79].Several studies elucidated the role of BDNF in memory mod-ulation by tDCS. In fact, it was reported that anodal currentscould increase BDNF expression [68], and its activation viatropomyosin receptor kinase (Trk) receptors [80], triggeringNMDAR opening, and inducing a later phase LTP (L-LTP)facilitation [81]. Accordingly, Yu et al. [41] found that theadministration the Trk inhibitor ANA-12 prevented theanodal tDCS-induced hippocampal CA1 LTP increase. Otherstudies, using the same polarity currents, revealed a linkbetween the upregulation of BDNF and cAMP response ele-ment binding protein/CREB-binding protein (CREB/CBP)[40] involved in LTP and memory formation [82]. Also, theapplication of cortical anodal currents in frontal cortex wasable to upregulate BDNF together with striatal dopamine[33]. The upregulation of BDNF following neurostimulationwas associated with the augmentation of expression levels ofimmediate early genes (IEGs), such as c-fos and zif268 [69].Moreover, Kim et al. [78] confirmed that repetitive anodaltDCS in right sensorimotor cortex of healthy rats promoteda significant increase of mRNA levels of plasticity-associated genes, namely, BDNF, cAMP response elementbinding protein (CREB), synapsin I, Ca2+/calmodulin-dependent protein kinase II (CaMKII), activity-regulatedcytoskeleton-associated protein (Arc), and c-fos. It was alsodemonstrated that sensory evoked cortical responses wereboosted after tDCS via alpha-1 adrenergic receptor-mediated astrocytic Ca2+/IP3 signaling, thus involving alsoglia and the adrenergic system [75]. Anodal tDCS actionsin glia were further confirmed by Mishima et al. [76]. Usinga mouse model lacking Ca2+ uptake in astrocytes, the inositoltrisphosphate receptor type 2 (IP3R2) knockout (KO) mouseand also an adrenergic receptor antagonist, they confirmeddecreased microglia motility along with soma enlargementin tDCS stimulated animals [76].
In poststroke recovery, it was found that anodal currentssignificantly increased the GAP-43 and the microtubule-associated protein 2 (MAP-2) expression around the infarctarea [56]. These neuronal growth-promoting proteins areoverexpressed during dendritic remodeling and axonalregrowth throughout the acute phase of stroke [83, 84].Anodal stimulation also modulated pannexin-1 (PX1) hemi-channel levels [85, 86] and, following an ischemic insult, neu-rostimulation decreased rat PX1 mRNA and, consequently,augmented dendritic spine density in the surrounding areasof cerebral infarction; these cellular outcomes were associ-ated with the improvement of motor function [85]. Someauthors proposed that tDCS-induced improvement of stro-ke/TBI symptoms might be due to increase of BDNF expres-
sion and associated with choline/creatine ratios in theperilesional cortex [31].
Overall, tDCS methodology was able to modulate molec-ular pathways involved in the regulation of cognition-relatedsynaptic plasticity mechanisms (Figure 3). The revised in vivoanimal studies regarding tDCS-induced effects in the cellularand molecular mechanisms of memory and learning arelisted in Table 4.
4. Discussion
This systematic review collected several studies that confirmthe potential effects of tDCS on neuronal activity and synap-tic plasticity. Here, we documented a variable combination ofstimulation protocols, stimulation areas, and healthy and dis-ease animal models. Most of the existent literature is focusedon human application of tDCS. The comprehensive revisionof the effect of tDCS on rodent models of normal and patho-logical brain functioning does therefore provide a novel con-tribution to the field. Overall, the revised studies indicatedthat tDCS was able to modulate synaptic plasticity and, con-sequently, learning and memory processes [87, 88].
Memory formation and consolidation are recognized torely on activity-dependent modifications, such as LTD andLTP [89], both dependent on the activation of calcium-dependent kinases (e.g., CaMKs), which in turn control thetrafficking of NMDARs and AMPARs [90]. Despite the wideset of stimulation protocols, tDCS-induced modulation ofNMDAR signaling and synaptic protein upregulation result-ing in LTP and cognitive enhancement have been consis-tently reported in animal studies. Anodal tDCS increasedAMPAR synapse translocation [73, 89] and induced spatialmemory improvement by involving both CREB and BDNFexpression alterations [53]. Also, an increase in hippocampaland cortical mRNA levels of c-fos, synapsin, CaMKII, andArc was observed poststimulation [78].
Similar results highlighting tDCS effects in neuroplasti-city were obtained with in vitro studies. Accordingly, Ranieriand coworkers [69] probed that anodal currents increasedNMDAR-dependent LTP in hippocampal CA3-CA1 synap-ses [69], in part, due to production of BDNF [68]. In addi-tion, it was demonstrated that tDCS-induced hippocampalBDNF release is dependent on histone acetylation of BDNFgene promoters [40]. Overall, the abovementioned worksprovide positive evidence for the effect of tDCS on cognitivefunction enhancement.
Although tDCS impaired the acquisition of both contextualand cued fear memory [39], there are no studies on possiblecascades/proteins involved in tDCS-induced neuroplasticityalterations following fear memory changes. Nevertheless, avery recent paper demonstrated chronic repetitive TMS ofthe ventromedial prefrontal cortex reversed stress-inducedbehavior impairments with an increase of c-fos activity [91].
Cortical anodal currents have been shown to be mostlyexcitatory and support memory enhancement and neuro-plasticity. The literature is also consistent with the notionthat the stimulation over the cortical region functionallyinvolved in a certain cognitive task increases performancein that specific task. Marshall et al. demonstrated that anodal
15Neural Plasticity
currents over the PFC, a region involved in memory encod-ing, during slow wave sleep improved declarative memory[28]. However, it was described that cortical cathodal stimu-lation simultaneously with training task was able to increasevisuospatial working memory, in spite of the fact that it wasassociated with decreased excitability [42]. This suggests thatmodulatory effects of tDCS were influenced by the polarity-dependent electrical dynamics established between the stim-ulated area and its related neuronal networks. In agreement,a recent report observed an inhibitory effect in motor learn-ing tasks following anodal currents in the cerebellum; theanodal excitatory effect over the Purkinje cell activity ledto an overall inhibition of downstream structures, reducingas a result the vestibulo-ocular reflex gain [90]. Similar par-adoxical results have been observed in humans. Recently,Moliadze and collaborators [92] reported that tDCS-induced neural modulation depended on several parame-ters, namely, the age. In fact, an excitatory effect was seenin young subjects, but not in the older participants.
Nowadays, TMS, another important noninvasive brainstimulation technique, is useful for evaluating excitability inthe primary motor cortex (M1) and conductivity along thecortical-spinal tract. This technique has been amply used inrehabilitation of stroke patients [93] and in neuropsychiatric
disorders, namely, depression [94]. tDCS and TMS areundergoing the most active investigation and share a capacityto modulate regional cortical excitability, and both are well-tolerated by children and adults [95]. However, TMS hasbeen already approved for clinical use and tDCS is stillundergoing investigation as a plausible therapy for a rangeof neuropsychiatric disorders [95]. The rational, in part, forthis is because data on the efficacy and safety of tDCS aresparse and employ heterogeneous stimulation protocols.Indeed, there is a paucity of strictly conducted randomized,sham controlled clinical trials, and case considerable follow-up periods, which makes it difficult to use these results toinform clinical practice concerning the putative beneficial roleof tDCS. Moreover, tDCS effects seem to be clearly dependenton structure, connectivity, and function of the target brainregion. Importantly, these outcomes were intrinsically corre-lated with GABAergic neurotransmission which raises theissue that one has to take into account that during develop-ment GABA can act as an excitatory neurotransmitter [96].
5. Conclusions
There is growing evidence that tDCSmodulates brain activityand, consequently, enhances synaptic plasticity and cognitive
Postsynaptic neuron
Early genesBdnf
mTOR
Protein kinasesP
AMPA receptorNMDA receptor
BDNFTrkB receptor
Anodal tDCS
Synaptic cle� Behavioral changes
LTP facilitatation
Formation of new protein (BDNF)
GSK3Ca2+
Ca2+
Figure 3: Schematic illustration of molecular mechanisms underlying the effect of anodal transcranial direct current stimulation (tDCS) onneuronal physiology. The neurostimulation in the target cortical area depolarizes neuronal membrane and glutamate released in presynapticneuron and binds in NMDA and AMPA receptors (see book chapter Rozisky et al., 2015). Consequently, there is intracellular Ca2+
upregulation in the postsynaptic neuron, which can activate protein kinases that in turn modulate numerous neuronal signaling pathways(such as the mTOR pathway) leading to transcriptional changes. The tDCS also activates molecular cascades to promote BDNFproduction. As a long-term mechanism, gene transcription is modulated leading to the formation of new proteins that in turn lead tofacilitation of LTP and improvement of cognition. Abbreviations: AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF:brain-derived neurotrophic factor; CBP: CREB-binding protein; CREB: cAMP response element binding protein; GSK3: glycogen synthasekinase 3; LTP: long-term potentiation; mTOR: mammalian target of rapamycin; NMDA: N-methyl-D-aspartate; TrkB: tropomyosinreceptor kinase B.
16 Neural Plasticity
Table4:Cellularandmolecular
mechanism
sun
derlying
transcranialdirectcurrentstim
ulationeffectin
thebrain.
Autho
rYear
Animal
mod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Márqu
ez-
Ruizet.
[63]
2012
NDM
New
Zealand
White
albino
rabbits;
N/A
13a-tD
CS
and
c-tD
CS
Somatosensory
cortex
(S1)
0.5;1;1.5
and2
0.7857
103.7
Ear
35N
N(single
session)
↑LF
Pin
S1(a-tDCS)
and↓LF
PS1
(c-tDCS)
Roh
anetal.[57]
2015
NDM
Sprague
Daw
ley
rats;m
ale
34a-tD
CS
SCdo
rsalto
the
hippocam
pus
0.1or
0.25
0.25
30N/A
Between
shou
lders
8.04
NN
(single
session)
#LT
PandPPFin
the
hippocam
pus
Yoon
etal.[31]
2016
Lateral
fluid
percussion
metho
d
Sprague
Daw
ley
rats;m
ales
36a-tD
CS
Hippocampu
s0.2
0.0225
2028.2
Chest
48(corset)
YY(dailyfor
5days)
#perilesion
alarea
BDNFexpression
(tDCS2weeks
post-TBI)
#choline/creatinine
ratios
(tDCS1week
post-TBI)
Motor
performance
recovery
(2weeks
oftD
CS)
Leffa
etal.[33]
2016
SHR
SHRrats
andWKT
rats;m
ales
48a-tD
CS
Fron
talcortex
0.5
1.5
2033.4
Between
ears
1.5
NY(8
consecutive
days
#DAlevelsin
STRin
both
ratstrainsandin
thehipp
ocam
pus
followingtD
CS
treatm
entin
WKY
#BDNFlevelsin
WKY
rats
Short-term
mem
ory
improvem
ent
Pod
daetal.[40]
2016
NDM
C57BL/6
mice;
males
16a-tD
CS
vs.
c-tD
CS
Leftparietal
cortex
(dorsal
tohipp
ocam
pal
form
ation)
0.35
0.06
20N/A
Ventral
thorax
5.2
NN
(single
session)
#spatiallearningand
mem
ory(a-tDCS);
benefitsobservable
oneweekafter
#BDNFexpression
inthehippocam
pus
CREB/CBPpathway
activation
17Neural Plasticity
Table4:Con
tinu
ed.
Autho
rYear
Animal
mod
elSpecim
en;
gend
erN
Stim
ulationparameters
Mainfind
ings
Stim
ulationelectrod
eReference
electrod
e
Anesthesia
rtDCS
Polarity
Position
Stim
ulation
intensity
(mA)
Size
(cm
2 )
Stim
ulation
duration
(min)
Current
density
(A/m
2 )Position
Area
(cm
2 )
Mon
aietal.[75]
2016
NDM
G7N
G817
mice;N/A
10a-tD
CS
Primaryvisual
cortex
(VI)
0.1
0.02
10N/A
Neck
N/A
NN
(single
session)
Upto
50%
expansion
ofvisualevokeactive
area
(upto
2h
poststim
ulationeffect)
tDCS-indu
ced
plasticity
depend
son
theactivity
ofIP,R
2,andA1A
R
Kim
etal.
[78]
2017
NDM
Sprague
Daw
ley
rats;m
ales
90a-tD
CS
Right
sensorim
otor
cortex
0.25
0.071
20N/A
Right
anterior
chest
0.5
NY(7
days)
#BDNF,
CREB,
synapsin,and
CaM
KII
mRNAexpression
levels(ipsilateral
cortex)andc-fos
(hippocampu
s)
Stafford
etal.[73]
2018
NDM
Sprague
Daw
ley
rats,m
ales
16a-tD
CS
Caudalto
bregma
0.25
0.25
30N/A
Ventral
thorax
N/A
NN
(single
session)
↑AMPAR
translocationto
the
synapsein
the
hipp
ocam
pusand↑
phosph
orylationof
the
S831
siteon
GluA1
Martins
etal.[97]
2019
NDM
Male
Wistar
rats;m
ales
50a-tD
CS
LeftmPFC
0.4
N/A
13N/A
N/A
N/A
N/A
Y(5
days)
↑Spatialw
orking
mem
ory
↑GAP-43(extinctby
AMPARantagonist
PRP)
Yuetal.
[41]
2019
NDM
Sprague
Daw
ley
rats;m
ales
224
a-tD
CS
SCdo
rsalto
the
hippocam
pus
0.25
0.25
30N/A
Anterior
chest
N/A
(EEG
electrod
e)Y
N(single
session)
↑Mem
ory(passive
avoidancemem
ory
retention)
↑LT
Pin
CA1
hippocam
pus(blocked
byTrkBan
tagonist)
↑BDNFin
CA1
hippocam
pus
Abbreviations:rtD
CS:repetitive
transcranialdirectcurrentstimulation;a-tD
CS:anod
altranscranialdirectcurrentstimulation;c-tD
CS:cathod
altranscranialdirectcurrentstimulation;C57BL/6:mou
sestrain;SC:
stereotaxiccoordinates;NDM:n
odiseasemod
el;SHR:spo
ntaneous
hypertensive
rats;W
KY:W
istarKyoto
rats;P
FC:prefron
talcortex;mPFC
:medialp
refron
talcortex;dP
FC:dorsolateralp
refron
talcortex;DG:
dentategyrus;ST
R:striatum;S1:somatosensory
cortex;V
1:prim
aryvisualcortex;ITC:inferotem
poralcortex;CA1:cornuam
mon
is1region
inthehipp
ocam
pus;TBI:traumaticbraininjury;P
RP:peram
panel;
CREB:cAMPrespon
seelem
ent-bind
ingprotein(transcription
factor);CREB/CBP:cAMPrespon
seelem
entb
inding
protein;
BDNF:brain-derivedneurotroph
icfactor;D
A:dop
amine;GAP-43:grow
thassociate
protein43;C
aMKII:C
a2+/calmod
ulin-dependent
proteinkinase;m
RNA:m
essengerribonu
cleicacid;IP3R
2:inositoltripho
sphatetype
2receptor;A
1AR:adeno
sine
A2A
receptor;A
MPAR:α-amino-3-hydroxy-5-
methyl-4-isoxazolepropion
icacidreceptor;G
luA1:AMPAreceptor
subu
nitA
1;LF
P:localfieldpo
tential;LT
P:lon
g-term
potentiation
;PPF:paired
pulsefacilitation;EEG:eletroencephalography;A
/m2 :am
pereper
square
meter;m
A:m
illiampere;cm
2 :square
centim
eter;m
m:m
illim
eter;h
:hou
r;min:m
inute;vs.:versus;Y
:yes;N
:no;N/A
:not
available.
18 Neural Plasticity
performance. Overall, reports from laboratory animalresearch present tDCS as a promising noninvasive brainstimulation technique. The presented evidence is thereforeconsistent with human studies suggesting that this techniqueis useful to mitigate neurologic symptoms of several braindisorders, thus improving learning and memory. Furtherresearch is needed so that this technique can be fully trans-lated into optimal therapeutic strategies.
Conflicts of Interest
The authors declare that there is no conflict of interestregarding the publication of this paper.
Authors’ Contributions
Joana Gonçalves and Miguel Castelo-Branco share seniorauthorship.
Acknowledgments
This work was supported by grants POCI-01-0145-FEDER-016428 and CENTRO-01-0145-FEDER-000016 financed byCentro 2020 FEDER, COMPETE, FLAD Life Sciences Ed 22016, FCT/UID 4950 COMPETE, POCI-01-0145-FEDER-007440, FCT, and European Grant H2020 STIPED.
References
[1] G. Ruffini, F. Wendling, I. Merlet et al., “Transcranial currentbrain stimulation (tCS): models and technologies,” IEEETransactions on Neural Systems and Rehabilitation Engineer-ing, vol. 21, no. 3, pp. 333–345, 2013.
[2] M. A. Nitsche and W. Paulus, “Excitability changes inducedin the human motor cortex by weak transcranial direct cur-rent stimulation,” The Journal of Physiology, vol. 527, no. 3,pp. 633–639, 2000.
[3] T. Wagner, A. Valero-Cabre, and A. Pascual-Leone, “Nonin-vasive human brain stimulation,” Annual Review of Biomed-ical Engineering, vol. 9, no. 1, pp. 527–565, 2007.
[4] M. Nitsche, D. Liebetanz, A. Antal, N. Lang, F. Tergau, andW. Paulus, “Modulation of cortical excitability by weak directcurrent stimulation-technical, safety and functional aspects,”Supplements to Clinical Neurophysiology, vol. 56, pp. 255–276, 2003.
[5] P. Kellaway, “The part played by electrical fish in the earlyhistory of bioelectricity and electrotherapy,” Bulletin of theHistory of Medicine, vol. 20, no. 2, pp. 130–134, 1946.
[6] A. Parent, “Giovanni Aldini: from animal electricity tohuman brain stimulation,” The Canadian Journal of Neuro-logical Sciences, vol. 31, no. 4, pp. 576–584, 2004.
[7] T. Bullock and C. Terzuolo, “Diverse forms of activity in thesomata of spontaneous and integrating ganglion cells,” TheJournal of Physiology, vol. 138, no. 3, pp. 341–364, 1957.
[8] C. Poreisz, K. Boros, A. Antal, and W. Paulus, “Safety aspectsof transcranial direct current stimulation concerning healthysubjects and patients,” Brain Research Bulletin, vol. 72, no. 4-6, pp. 208–214, 2007.
[9] L. Bindman, O. Lippold, and J. Redfearn, “The action of briefpolarizing currents on the cerebral cortex of the rat (1) duringcurrent flow and (2) in the production of long-lasting after-
effects,” The Journal of Physiology, vol. 172, pp. 369–382,1964.
[10] C. A. Terzuolo and T. H. Bullock, “Measurement of imposedvoltage gradient adequate to modulate neuronal firing,” Pro-ceedings of the National Academy of Sciences of the UnitedStates of America, vol. 42, no. 9, pp. 687–694, 1956.
[11] M. A. Nitsche and W. Paulus, “Sustained excitability eleva-tions induced by transcranial DC motor cortex stimulationin humans,” Neurology, vol. 57, no. 10, pp. 1899–1901,2001.
[12] A. Antal, D. Terney, C. Poreisz, and W. Paulus, “Towardsunravelling task-related modulations of neuroplastic changesinduced in the human motor cortex,” The European Journalof Neuroscience, vol. 26, no. 9, pp. 2687–2691, 2007.
[13] B. Krause and R. Cohen Kadosh, “Not all brains are createdequal: the relevance of individual differences in responsive-ness to transcranial electrical stimulation,” Frontiers in Sys-tems Neuroscience, vol. 8, 2014.
[14] M. Bikson, A. Rahman, and A. Datta, “Computationalmodels of transcranial direct current stimulation,” ClinicalEEG and Neuroscience, vol. 43, no. 3, pp. 176–183, 2012.
[15] A. Fertonani and C. Miniussi, “Transcranial electrical stimu-lation: what we know and do not know about mechanisms,”The Neuroscientist, vol. 23, no. 2, pp. 109–123, 2017.
[16] D. Liebetanz, F. Klinker, D. Hering et al., “Anticonvulsanteffects of transcranial direct-current stimulation (tDCS) inthe rat cortical ramp model of focal epilepsy,” Epilepsia,vol. 47, no. 7, pp. 1216–1224, 2006.
[17] D. Liebetanz, R. Koch, S. Mayenfels, F. König, W. Paulus, andM. A. Nitsche, “Safety limits of cathodal transcranial directcurrent stimulation in rats,” Clinical Neurophysiology,vol. 120, no. 6, pp. 1161–1167, 2009.
[18] M. Jackson, D. Truong, M. Brownlow et al., “Safety parameterconsiderations of anodal transcranial direct current stimula-tion in rats,” Brain, Behavior, and Immunity, vol. 64,pp. 152–161, 2017.
[19] M. Nitsche, L. Cohen, E. Wassermann et al., “Transcranialdirect current stimulation: state of the art 2008,” Brain Stim-ulation, vol. 1, no. 3, pp. 206–223, 2008.
[20] K. Monte-Silva, M. Kuo, D. Liebetanz, W. Paulus, andM. A. Nitsche, “Shaping the optimal repetition interval forcathodal transcranial direct current stimulation (tDCS),”Journal of Neurophysiology, vol. 103, no. 4, pp. 1735–1740,2010.
[21] P. S. Boggio, R. Ferrucci, S. P. Rigonatti et al., “Effects oftranscranial direct current stimulation on working memoryin patients with Parkinson's disease,” Journal of the Neurolog-ical Sciences, vol. 249, no. 1, pp. 31–38, 2006.
[22] M. Horiba, Y. Ueki, I. Nojima et al., “Impaired motor skillacquisition using mirror visual feedback improved by trans-cranial direct current stimulation (tDCS) in patients withParkinson’s disease,” Frontiers in Neuroscience, vol. 13,p. 602, 2019.
[23] F. Fregni, P. S. Boggio, M. A. Nitsche, S. P. Rigonatti, andA. Pascual-Leone, “Cognitive effects of repeated sessions oftranscranial direct current stimulation in patients withdepression,” Depression and Anxiety, vol. 23, no. 8, pp. 482–484, 2006.
[24] F. Fregni, P. Boggio, C. Mansur et al., “Transcranial directcurrent stimulation of the unaffected hemisphere in strokepatients,” Neuroreport, vol. 16, no. 14, pp. 1551–1555, 2005.
19Neural Plasticity
[25] F. Hummel, P. Celnik, P. Giraux et al., “Effects of non-invasive cortical stimulation on skilled motor function inchronic stroke,” Brain, vol. 128, no. 3, pp. 490–499, 2005.
[26] M. C.W. English, E. S. Kitching, M. T. Maybery, and T. A. W.Visser, “Modulating attentional biases of adults with autistictraits using transcranial direct current stimulation: a pilotstudy,” Autism Research, vol. 11, no. 2, pp. 385–390, 2018.
[27] J. Kang, E. Cai, J. Han et al., “Transcranial direct current stim-ulation (tDCS) can modulate EEG complexity of childrenwith autism spectrum disorder,” Frontiers in Neuroscience,vol. 12, p. 201, 2018.
[28] L. Marshall, M. Mölle, M. Hallschmid, and J. Born, “Trans-cranial direct current stimulation during sleep improvesdeclarative memory,” Journal of Neuroscience, vol. 24,no. 44, pp. 9985–9992, 2004.
[29] J. C. de Souza Custódio, C. W. Martins, M. D. M. V. Lugon,F. Fregni, and E. M. Nakamura-Palacios, “Epidural directcurrent stimulation over the left medial prefrontal cortexfacilitates spatial working memory performance in rats,”Brain Stimulation, vol. 6, no. 3, pp. 261–269, 2013.
[30] X. Yu, Y. Li, H. Wen, Y. Zhang, and X. Tian, “Intensity-dependent effects of repetitive anodal transcranial direct cur-rent stimulation on learning and memory in a rat model ofAlzheimer’s disease,” Neurobiology of Learning and Memory,vol. 123, pp. 168–178, 2015.
[31] K. J. Yoon, Y. T. Lee, S. W. Chae, C. R. Park, and D. Y. Kim,“Effects of anodal transcranial direct current stimulation(tDCS) on behavioral and spatial memory during the earlystage of traumatic brain injury in the rats,” Journal of theNeurological Sciences, vol. 362, pp. 314–320, 2016.
[32] T. Kamida, S. Kong, N. Eshima, T. Abe, M. Fujiki, andH. Kobayashi, “Transcranial direct current stimulationdecreases convulsions and spatial memory deficits followingpilocarpine-induced status epilepticus in immature rats,”Behavioural Brain Research, vol. 217, no. 1, pp. 99–103, 2011.
[33] D. T. Leffa, A. de Souza, V. L. Scarabelot et al., “Transcranialdirect current stimulation improves short-term memory inan animal model of attention-deficit/hyperactivity disorder,”European Neuropsychopharmacology, vol. 26, no. 2, pp. 368–377, 2016.
[34] D. Moher, A. Liberati, J. Tetzlaff, D. G. Altman, and ThePRISMA Group, “Preferred reporting items for systematicreviews and meta-analyses: the PRISMA statement,” PLoSMedicine, vol. 6, no. 7, article e1000097, 2009.
[35] M. R. Krause, T. P. Zanos, B. A. Csorba et al., “Transcranialdirect current stimulation facilitates associative learning andalters functional connectivity in the primate brain,” CurrentBiology, vol. 27, no. 20, pp. 3086–3096.e3, 2017.
[36] F. Manteghi, M. Nasehi, and M. Zarrindast, “Precondition ofright frontal region with anodal tDCS can restore the fearmemory impairment induced by ACPA in male mice,”EXCLI Journal, vol. 16, pp. 1–13, 2017.
[37] M. Nasehi, R. Soltanpour, M. Ebrahimi-Ghiri, S. Zarrabian,and M. R. Zarrindast, “Interference effects of transcranialdirect current stimulation over the right frontal cortex andadrenergic system on conditioned fear,” Psychopharmacol-ogy, vol. 234, no. 22, pp. 3407–3416, 2017.
[38] M. Nasehi, M. Khani-Abyaneh, M. Ebrahimi-Ghiri, andM. R. Zarrindast, “The effect of left frontal transcranialdirect-current stimulation on propranolol-induced fearmemory acquisition and consolidation deficits,” BehaviouralBrain Research, vol. 331, pp. 76–83, 2017.
[39] S. Abbasi, M. Nasehi, H. R. S. Lichaei, and M. R. Zarrindast,“Effects of left prefrontal transcranial direct current stimula-tion on the acquisition of contextual and cued fear memory,”Iranian Journal of Basic Medical Sciences, vol. 20, no. 6,pp. 623–630, 2017.
[40] M. Podda, S. Cocco, A. Mastrodonato et al., “Anodal trans-cranial direct current stimulation boosts synaptic plasticityandmemory in mice via epigenetic regulation of Bdnf expres-sion,” Scientific Reports, vol. 6, p. 22180, 2016.
[41] T. H. Yu, Y. J. Wu, M. E. Chien, and K. S. Hsu, “Transcranialdirect current stimulation induces hippocampal metaplasti-city mediated by brain-derived neurotrophic factor,” Neuro-pharmacology, vol. 144, no. 1, pp. 358–367, 2019.
[42] C. Dockery, D. Liebetanz, N. Birbaumer, M. Malinowska, andM. J. Wesierska, “Cumulative benefits of frontal transcranialdirect current stimulation on visuospatial working memorytraining and skill learning in rats,” Neurobiology of Learningand Memory, vol. 96, no. 3, pp. 452–460, 2011.
[43] S. Yu, S. Park, and K. Sim, “The effect of tDCS on cognitionand neurologic recovery of rats with Alzheimer’s disease,”Journal of Physical Therapy Science, vol. 26, no. 2, pp. 247–249, 2014.
[44] C. H. Chang, H. Y. Lane, and C. H. Lin, “Brain stimulation inAlzheimer’s disease,” Frontiers in Psychiatry, vol. 9, 2018.
[45] A. Roostaei, G. Vaezi, M. Nasehi, A. Haeri-Rohani, and M. R.Zarrindast, “The Involvement of D1 and D2 dopamine recep-tors in the restoration effect of left frontal anodal, but notcathodal, tDCS on streptozocin-induced amnesia,” Archivesof Iranian Medicine, vol. 22, no. 3, pp. 144–154, 2019.
[46] Y.Wu, C. Lin, C. Yeh et al., “Repeated transcranial direct cur-rent stimulation improves cognitive dysfunction and synapticplasticity deficit in the prefrontal cortex of streptozotocin-induced diabetic rats,” Brain Stimulation, vol. 10, no. 6,pp. 1079–1087, 2017.
[47] D. T. Leffa, B. Bellaver, A. A. Salvi et al., “Transcranial directcurrent stimulation improves long-term memory deficits inan animal model of attention-deficit/hyperactivity disorderand modulates oxidative and inflammatory parameters,”Brain Stimulation, vol. 11, no. 4, pp. 743–751, 2018.
[48] O. Bragina, D. Lara, E. Nemoto, C. W. Shuttleworth, O. V.Semyachkina-Glushkovskaya, and D. E. Bragin, “Increasesin microvascular perfusion and tissue oxygenation via vaso-dilatation after anodal transcranial direct current stimulationin the healthy and traumatized mouse brain,” Advances inExperimental Medicine and Biology, vol. 1072, pp. 27–31,2018.
[49] P. Spagnolo and D. Goldman, “Neuromodulation interven-tions for addictive disorders: challenges, promise and road-map for future research,” Brain, vol. 140, no. 5, pp. 1183–1203, 2017.
[50] S. Pedron, J. Monnin, E. Haffen, D. Sechter, and V. vanWaes,“Repeated transcranial direct current stimulation preventsabnormal behaviors associated with abstinence from chronicnicotine consumption,” Neuropsychopharmacology, vol. 39,no. 4, pp. 981–988, 2014.
[51] S. Pedron, J. Beverley, E. Haffen, P. Andrieu, H. Steiner, andV. van Waes, “Transcranial direct current stimulation pro-duces long-lasting attenuation of cocaine-induced behavioralresponses and gene regulation in corticostriatal circuits,”Addiction Biology, vol. 22, no. 5, pp. 1267–1278, 2017.
[52] T. Kamida, S. Kong, N. Eshima, and M. Fujiki, “Cathodaltranscranial direct current stimulation affects seizures and
20 Neural Plasticity
cognition in fully amygdala- kindled rats,” NeurologicalResearch, vol. 35, no. 6, pp. 602–607, 2013.
[53] M. Zobeiri and G. van Luijtelaar, “Noninvasive transcranialdirect current stimulation in a genetic absence model,” Epi-lepsy & Behavior, vol. 26, no. 1, pp. 42–50, 2013.
[54] S. C. Dhamne, D. Ekstein, Z. Zhuo et al., “Acute seizure sup-pression by transcranial direct current stimulation in rats,”Annals of Clinical and Translational Neurology, vol. 2,no. 8, pp. 843–856, 2015.
[55] J. G. Rohan, K. A. Carhuatanta, S. M. McInturf, M. K.Miklasevich, and R. Jankord, “Modulating hippocampalplasticity with in vivo brain stimulation,” The Journal ofNeuroscience, vol. 35, no. 37, pp. 12824–12832, 2015.
[56] E. Gondard, M. Soto-Montenegro, A. Cassol, A. M. Lozano,and C. Hamani, “Transcranial direct current stimulation doesnot improve memory deficits or alter pathological hallmarksin a rodent model of Alzheimer’s disease,” Journal of Psychi-atric Research, vol. 114, pp. 93–98, 2019.
[57] K. J. Yoon, B. M. Oh, and D. Y. Kim, “Functional improve-ment and neuroplastic effects of anodal transcranial directcurrent stimulation (tDCS) delivered 1 day vs. 1 week aftercerebral ischemia in rats,” Brain Research, vol. 1452,pp. 61–72, 2012.
[58] D. Hebb, The Organization of Behavior, Wiley, New York,1949.
[59] M. Rueger, M. Keuters, M. Walberer et al., “Multi-sessiontranscranial direct current stimulation (tDCS) elicits inflam-matory and regenerative processes in the rat brain,” PLoSOne, vol. 7, no. 8, article e43776, 2012.
[60] L. Peruzzotti-Jametti, M. Cambiaghi, M. Bacigaluppi et al.,“Safety and efficacy of transcranial direct current stimulationin acute experimental ischemic stroke,” Stroke, vol. 44, no. 11,pp. 3166–3174, 2013.
[61] C. McCaig, L. Sangster, and R. Stewart, “Neurotrophinsenhance electric field-directed growth cone guidance anddirected nerve branching,” Developmental Dynamics,vol. 217, no. 3, pp. 299–308, 2000.
[62] A. Pikhovych, N. P. Stolberg, L. Jessica Flitsch et al., “Trans-cranial direct current stimulation modulates neurogenesisand microglia activation in the mouse brain,” Stem CellsInternational, vol. 2016, 9 pages, 2016.
[63] J. Márquez-Ruiz, R. Leal-Campanario, R. Sánchez-Campusano et al., “Transcranial direct-current stimula-tion modulates synaptic mechanisms involved in associativelearning in behaving rabbits,” Proceedings of the NationalAcademy of Sciences of the United States of America,vol. 109, no. 17, pp. 6710–6715, 2012.
[64] B. Krause, J. Márquez-Ruiz, and R. C. Kadosh, “The effect oftranscranial direct current stimulation: a role for corticalexcitation/inhibition balance?,” Frontiers in Human Neuro-science, vol. 7, no. 602, 2013.
[65] D. Antonenko, F. Schubert, F. Bohm et al., “tDCS-inducedmodulation of GABA levels and resting-state functional con-nectivity in older adults,” The Journal of Neuroscience, vol. 37,no. 15, pp. 4065–4073, 2017.
[66] C. Stagg and M. Nitsche, “Physiological basis of transcranialdirect current stimulation,” The Neuroscientist, vol. 17,no. 1, pp. 37–53, 2011.
[67] C. J. Stagg, V. Bachtiar, U. Amadi et al., “Local GABAconcentration is related to network-level resting functionalconnectivity,” eLife, vol. 3, no. 3, pp. 1–9, 2014.
[68] B. Fritsch, J. Reis, K. Martinowich et al., “Direct currentstimulation promotes BDNF-dependent synaptic plasticity:potential implications for motor learning,” Neuron, vol. 66,no. 2, pp. 198–204, 2010.
[69] F. Ranieri, M. Podda, E. Riccardi et al., “Modulation of LTP atrat hippocampal CA3-CA1 synapses by direct current stimu-lation,” Journal of Neurophysiology, vol. 107, no. 7, pp. 1868–1880, 2012.
[70] G. Kronberg, M. Bridi, T. Abel, M. Bikson, and L. C. Parra,“Direct current stimulation modulates LTP and LTD: activitydependence and dendritic effects,” Brain Stimulation, vol. 10,no. 1, pp. 51–58, 2017.
[71] Y. Sun, J. Lipton, L. Boyle et al., “Direct current stimulationinduces mGluR5-dependent neocortical plasticity,” Annalsof Neurology, vol. 80, no. 2, pp. 233–246, 2016.
[72] C. Lüscher and R. Malenka, “NMDA receptor-dependentlong-term potentiation and long-term depression (LTP/LTD),”Cold Spring Harbor Perspectives in Biology, vol. 4, no. 6,p. a005710, 2012.
[73] J. Stafford, M. Brownlow, A. Qualley, and R. Jankord,“AMPA receptor translocation and phosphorylation areinduced by transcranial direct current stimulation in rats,”Neurobiology of Learning and Memory, vol. 150, pp. 36–41,2018.
[74] S. Perret, A. Cantereau, J. Audin, B. Dufy, andD. Georgescauld, “Interplay between Ca2+ release and Ca2+
influx underlies localized hyperpolarization-induced [Ca2+]iwaves in prostatic cells,” Cell Calcium, vol. 25, no. 4,pp. 297–311, 1999.
[75] H. Monai, M. Ohkura, M. Tanaka et al., “Calcium imagingreveals glial involvement in transcranial direct currentstimulation-induced plasticity in mouse brain,” Nature Com-munications, vol. 7, p. 11100, 2016.
[76] T. Mishima, T. Nagai, K. Yahagi et al., “Transcranial directcurrent stimulation (tDCS) induces adrenergic receptor-dependent microglial morphological changes in mice,”eNeuro, vol. 6, no. 5, pp. 1–12, 2019.
[77] P. Opazo, S. Labrecque, C. Tigaret et al., “CaMKII triggers thediffusional trapping of surface AMPARs through phosphor-ylation of stargazin,” Neuron, vol. 67, no. 2, pp. 239–252,2010.
[78] M. S. Kim, H. Koo, S. W. Han et al., “Repeated anodaltranscranial direct current stimulation induces neuralplasticity-associated gene expression in the rat cortex andhippocampus,” Restorative Neurology and Neuroscience,vol. 35, no. 2, pp. 137–146, 2017.
[79] G. Leal, C. Bramham, and C. Duarte, “BDNF and hippocam-pal synaptic plasticity,” Vitamins and Hormones, vol. 104,pp. 153–195, 2017.
[80] C. McCaig, A. Rajnicek, B. Song, and M. Zhao, “Controllingcell behavior electrically: current views and future potential,”Physiological Reviews, vol. 85, no. 3, pp. 943–978, 2005.
[81] L. Minichiello, “TrkB signalling pathways in LTP and learn-ing,” Nature Reviews Neuroscience, vol. 10, no. 12, pp. 850–860, 2009.
[82] C. M. Alberini, “Transcription factors in long-term memoryand synaptic plasticity,” Physiological Reviews, vol. 89, no. 1,pp. 121–145, 2009.
[83] S. T. Carmichael, I. Archibeque, L. Luke, T. Nolan, J. Momiy,and S. Li, “Growth-associated gene expression after stroke:evidence for a growth- promoting region in peri-infarct
21Neural Plasticity
cortex,” Experimental Neurology, vol. 193, no. 2, pp. 291–311,2005.
[84] Y. Li, N. Jiang, C. Powers, and M. Chopp, “Neuronal damageand plasticity identified by microtubule-associated protein 2,growth-associated protein 43, and cyclin D1 immunoreactiv-ity after focal cerebral ischemia in rats,” Stroke, vol. 29, no. 9,pp. 1972–1981, 1998.
[85] T. Jiang, R. X. Xu, A. W. Zhang et al., “Effects of transcranialdirect current stimulation on hemichannel pannexin-1 andneural plasticity in rat model of cerebral infarction,” Neuro-sciences, vol. 226, pp. 421–426, 2012.
[86] P. Bargiotas, H. Monyer, and M. Schwaninger, “Hemichan-nels in cerebral ischemia,” Current Molecular Medicine,vol. 9, no. 2, pp. 186–194, 2009.
[87] L. Dimov, A. Franciosi, A. Campos, A. R. Brunoni, and R. L.Pagano, “Top-down effect of direct current stimulation onthe nociceptive response of rats,” PLoS One, vol. 11, no. 4,article e0153506, 2016.
[88] M. Rioult-Pedotti, D. Friedman, and J. Donoghue, “Learning-induced LTP in neocortex,” Science, vol. 290, no. 5491,pp. 533–536, 2000.
[89] R. Malenka and M. Bear, “LTP and LTD: an embarrassmentof riches,” Neuron, vol. 44, no. 1, pp. 5–21, 2004.
[90] J. Lisman, K. Cooper, M. Sehgal, and A. J. Silva, “Memory for-mation depends on both synapse-specific modifications ofsynaptic strength and cell-specific increases in excitability,”Nature Neuroscience, vol. 21, no. 3, pp. 309–314, 2018.
[91] M. Legrand, R. Troubat, B. Brizard, A. M. le Guisquet,C. Belzung, and W. el-Hage, “Prefrontal cortex rTMSreverses behavioral impairments and differentially activatesc-Fos in a mouse model of post-traumatic stress disorder,”Brain Stimulation, vol. 12, no. 1, pp. 87–95, 2019.
[92] V. Moliadze, E. Lyzhko, T. Schmanke, S. Andreas, C. M.Freitag, and M. Siniatchkin, “1 mA cathodal tDCS showsexcitatory effects in children and adolescents: insights fromTMS evoked N100 potential,” Brain Research Bulletin,vol. 140, pp. 43–51, 2018.
[93] F. Fisicaro, G. Lanza, A. A. Grasso et al., “Repetitive trans-cranial magnetic stimulation in stroke rehabilitation: reviewof the current evidence and pitfalls,” Therapeutic Advancesin Neurological Disorders, vol. 12, p. 1756286419878317,2019.
[94] M. Cantone, A. Bramanti, G. Lanza et al., “Cortical plasticityin depression,” ASN Neuro, vol. 9, no. 3, 2017.
[95] U. Palm, F. M. Segmiller, A. N. Epple et al., “Transcranialdirect current stimulation in children and adolescents: a com-prehensive review,” Journal of Neural Transmission (Vienna),vol. 123, no. 10, pp. 1219–1234, 2016.
[96] X. Leinekugel, I. Khalilov, H. McLean et al., “GABA is theprincipal fast-acting excitatory transmitter in the neonatalbrain,” Advances in Neurology, vol. 79, pp. 189–201, 1999.
[97] C. W. Martins, L. C. de Melo Rodrigues, M. A. Nitsche, andE. M. Nakamura-Palacios, “AMPA receptors are involved inprefrontal direct current stimulation effects on long-termworking memory and GAP-43 expression,” BehaviouralBrain Research, vol. 362, pp. 208–212, 2019.
[98] V. Nekhendzy, C. Fender, M. Davies et al., “The antinocicep-tive effect of transcranial electrostimulation with combineddirect and alternating current in freely moving rats,” Anesthe-sia and Analgesia, vol. 98, no. 3, pp. 730–7, table of contents,2004.
[99] N. O. B. Taib and M. Manto, “Trains of transcranial directcurrent stimulation antagonize motor cortex hypoexcitabilityinduced by acute hemicerebellectomy,” Journal of Neurosur-gery, vol. 111, no. 4, pp. 796–806, 2009.
[100] S. Kim, B. Kim, Y. Ko, M. S. Bang, M. H. Kim, and T. R. Han,“Functional and histologic changes after repeated transcra-nial direct current stimulation in rat stroke model,” Journalof Korean Medical Science, vol. 25, no. 10, pp. 1499–1505,2010.
[101] G. Laste, W. Caumo, L. Adachi et al., “After-effects of consec-utive sessions of transcranial direct current stimulation(tDCS) in a rat model of chronic inflammation,” Experimen-tal Brain Research, vol. 221, no. 1, pp. 75–83, 2012.
[102] L. N. S. Adachi, W. Caumo, G. Laste et al., “Reversal ofchronic stress-induced pain by transcranial direct currentstimulation (tDCS) in an animal model,” Brain Research,vol. 1489, pp. 17–26, 2012.
[103] F. Notturno, M. Pace, F. Zappasodi, E. Cam, C. L. Bassetti,and A. Uncini, “Neuroprotective effect of cathodal transcra-nial direct current stimulation in a rat stroke model,” Journalof the Neurological Sciences, vol. 342, no. 1-2, pp. 146–151,2014.
[104] C. Lu, Y. Wei, R. Hu, Y. Wang, K. Li, and X. Li, “TranscranialDirect Current Stimulation Ameliorates Behavioral Deficitsand Reduces Oxidative Stress in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Mouse Model of Parkinson'sDisease,” Neuromodulation, vol. 18, no. 6, pp. 442–447,2015.
[105] L. N. S. Adachi, A. S. Quevedo, A. de Souza et al., “Exoge-nously induced brain activation regulates neuronal activityby top-down modulation: conceptualized model for electricalbrain stimulation,” Experimental Brain Research, vol. 233,no. 5, pp. 1377–1389, 2015.
[106] Y.-H. Liu, L.-D. Liao, S. J. Chan, A. Bandla, and N. V. Thakor,“An integrated neuroprotective intervention for brain ische-mia validated by ECoG- fPAM,” in 2016 38th Annual Inter-national Conference of the IEEE Engineering in Medicineand Biology Society (EMBC), pp. 4009–4012, Orlando, FL,USA, Aug. 2016.
[107] R. Braun, R. Klein, H. Walter et al., “Transcranial direct cur-rent stimulation accelerates recovery of function, inducesneurogenesis and recruits oligodendrocyte precursors in arat model of stroke,” Experimental Neurology, vol. 279,pp. 127–136, 2016.
[108] S. G. Cioato, L. F. Medeiros, P. R. M. Filho et al., “Long-last-ing effect of transcranial direct current stimulation in thereversal of hyperalgesia and cytokine alterations induced bythe neuropathic pain model,” Brain Stimulation, vol. 9,no. 2, pp. 209–217, 2016.
[109] P. R. M. Filho, R. Vercelino, S. G. Cioato et al., “Transcranialdirect current stimulation (tDCS) reverts behavioralalterations and brainstem BDNF level increase inducedby neuropathic pain model: Long- lasting effect,” Prog-ress in Neuro-Psychopharmacology & Biological Psychia-try, vol. 64, pp. 44–51, 2016.
[110] S. F. da Silva Moreira, L. F. Medeiros, A. de Souza et al.,“Transcranial direct current stimulation (tDCS) neuromodu-latory effects on mechanical hyperalgesia and cortical BDNFlevels in ovariectomized rats,” Life Sciences, vol. 145,pp. 233–239, 2016.
[111] Y. Liu, S. Chan, H. Pan et al., “Integrated treatment modalityof cathodal-transcranial direct current stimulation with
22 Neural Plasticity
peripheral sensory stimulation affords neuroprotection in arat stroke model,” Neurophotonics, vol. 4, no. 4, article045002, 2017.
[112] C. Winkler, J. Reis, N. Hoffmann et al., “Anodal transcranialdirect current stimulation enhances survival and integrationof dopaminergic cell transplants in a rat Parkinson model,”eNeuro, vol. 4, no. 5, pp. 1–11, 2017.
[113] A. Souza, D. F. Martins, L. F. Medeiros et al., “Neurobiologi-cal mechanisms of antiallodynic effect of transcranial directcurrent stimulation (tDCS) in a mice model of neuropathicpain,” Brain Research, vol. 1682, pp. 14–23, 2018.
[114] F. Paciello, M. V. Podda, R. Rolesi et al., “Anodal transcranialdirect current stimulation affects auditory cortex plasticity innormal-hearing and noise-exposed rats,” Brain Stimulation,vol. 11, no. 5, pp. 1008–1023, 2018.
[115] F. Fregni, I. Macedo, L. Spezia-Adachi et al., “Transcranialdirect current stimulation (tDCS) prevents chronic stress-induced hyperalgesia in rats,” Brain Stimulation, vol. 11,no. 2, pp. 299–301, 2018.
[116] S. Lee, J. Youn, W. Jang, and H. O. Yang, “Neuroprotec-tive effect of anodal transcranial direct current stimulationon 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice through modulating mito-chondrial dynamics,” Neurochemistry International, vol. 129,p. 104491, 2019.
[117] E. M. M. Callai, V. L. Scarabelot, L. Fernandes Medeiros et al.,“Transcranial direct current stimulation (tDCS) and trigemi-nal pain: a preclinical study,” Oral Diseases, vol. 25, no. 3,pp. 888–897, 2019.
[118] V. Scarabelot, C. de Oliveira, L. Medeiros et al., “Transcranialdirect-current stimulation reduces nociceptive behaviour inan orofacial pain model,” Journal of Oral Rehabilitation,vol. 46, no. 1, pp. 40–50, 2019.
23Neural Plasticity