brain

sciences
Review
Neural Mechanisms of Neuro-Rehabilitation Using Transcranial
Direct Current Stimulation (tDCS) over the Front-Polar Area
Koji Ishikuro 1 , Noriaki Hattori 1 , Hironori Otomune 1 , Kohta Furuya 1 , Takeshi Nakada 1 ,
Kenichiro Miyahara 2 , Takashi Shibata 3,4 , Kyo Noguchi 5 , Satoshi Kuroda 4 , Yuji Nakatsuji 6
and Hisao Nishijo 7, *

1 Department of Rehabilitation, Toyama University Hospital, Toyama 930-0194, Japan;

[email protected] (K.I.); [email protected] (N.H.);
[email protected] (H.O.); [email protected] (K.F.);
[email protected] (T.N.)
2 Department of Physical Therapy, Toyama College of Medical Welfare, Toyama 930-0194, Japan;
[email protected]
3 Department of Neurosurgery, Toyama Nishi General Hospital, Toyama 939-2716, Japan;
[email protected]
4 Department of Neurosurgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan;
[email protected]
5 Department of Radiology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan;
[email protected]
6 Department of Neurology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan;
[email protected]
7 Faculty of Human Sciences, University of East Asia, Shimonoseki 751-8503, Japan
* Correspondence: [email protected]; Tel.: +81-832561111

Abstract: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation (NIBS)
technique that applies a weak current to the scalp to modulate neuronal excitability by stimulating
the cerebral cortex. The technique can produce either somatic depolarization (anodal stimulation)
Citation: Ishikuro, K.; Hattori, N.;
or somatic hyperpolarization (cathodal stimulation), based on the polarity of the current used by
Otomune, H.; Furuya, K.; Nakada, T.;
Miyahara, K.; Shibata, T.; Noguchi,
noninvasively stimulating the cerebral cortex with a weak current from the scalp, making it a NIBS
K.; Kuroda, S.; Nakatsuji, Y.; et al. technique that can modulate neuronal excitability. Thus, tDCS has emerged as a hopeful clinical neuro-
Neural Mechanisms of rehabilitation treatment strategy. This method has a broad range of potential uses in rehabilitation
Neuro-Rehabilitation Using medicine for neurodegenerative diseases, including Parkinson’s disease (PD). The present paper
Transcranial Direct Current reviews the efficacy of tDCS over the front-polar area (FPA) in healthy subjects, as well as patients
Stimulation (tDCS) over the with PD, where tDCS is mainly applied to the primary motor cortex (M1 area). Multiple evidence
Front-Polar Area. Brain Sci. 2023, 13, lines indicate that the FPA plays a part in motor learning. Furthermore, recent studies have reported
1604. https://doi.org/10.3390/
that tDCS applied over the FPA can improve motor functions in both healthy adults and PD patients.
brainsci13111604
We argue that the application of tDCS to the FPA promotes motor skill learning through its effects on
Academic Editor: Farsin Hamzei the M1 area and midbrain dopamine neurons. Additionally, we will review other unique outcomes
of tDCS over the FPA, such as effects on persistence and motivation, and discuss their underlying
Received: 4 October 2023
neural mechanisms. These findings support the claim that the FPA could emerge as a new key brain
Revised: 30 October 2023
Accepted: 17 November 2023
region for tDCS in neuro-rehabilitation.
Published: 18 November 2023
Keywords: transcranial direct current stimulation; Parkinson’s disease; neural mechanisms; the
frontal pole area

Copyright: © 2023 by the authors.

Licensee MDPI, Basel, Switzerland.
This article is an open access article 1. Introduction
distributed under the terms and
conditions of the Creative Commons
Techniques for noninvasive brain stimulation (NIBS) have been widely used in both
Attribution (CC BY) license (https://
patients and healthy people. A more accurate description of NIBS is that it is a low-intensity
creativecommons.org/licenses/by/
transcranial stimulation to modulate cortical excitability. There are two well-known neuro-
4.0/). modulation therapies based on this strategy: repetitive transcranial magnetic stimulation

Brain Sci. 2023, 13, 1604. https://doi.org/10.3390/brainsci13111604 https://www.mdpi.com/journal/brainsci

Brain Sci. 2023, 13, 1604 2 of 15

(rTMS) and transcranial direct current stimulation (tDCS). rTMS applies magnetism to
modulate cortical excitability, while tDCS uses electrical stimulation instead. While rTMS
can stimulate the cortex with minimal reduction in stimulation intensity from the scalp,
it is essential for the patient’s head to be secured to a comfortable chair to ensure precise
stimulation of the region of interest (ROI). However, clinical situations can pose a challenge
for rTMS, as patients may often exhibit involuntary movements that hinder fixation of the
head position. Additionally, while it is infrequent, rTMS can cause harmful effects such as
seizures. Conversely, tDCS has advantages in hospital settings, such as ease of usage, fewer
adverse events, and high portability. Therefore, tDCS can be used in combination with
physical rehabilitation to enhance plastic changes in ongoing synapses activated during
physical rehabilitation [1,2]. Furthermore, recent research has consistently demonstrated
that the combination of tDCS and rehabilitation is more effective than utilizing tDCS alone
in the long-term improvement of neurological disease symptoms [1–6].
tDCS can safely modulate cortical activity in both acute (immediate) and after (chronic)
effects. In acute effects during stimulation, tDCS can modulate cortical neuronal activity.
For example, anodal stimulation can increase cortical excitability by depolarizing the soma
and basal dendrite of cortical pyramidal neurons (somatic hypothesis) [7]. On the other
hand, cathodal stimulation can produce opposite effects, i.e., hyperpolarization of the basal
dendrites and soma [8,9]. Consistent with the somatic hypothesis, firing rates of putative
pyramidal neurons were elevated by anodal stimulation and suppressed by cathodal stim-
ulation in monkeys [10]. However, firing rates of putative inhibitory neurons increased
with both anodal and cathodal stimulation (i.e., regardless of polarity). This is likely due
to network-mediated effects resulting from the modulation of other cell types [10]. In
after effects, tDCS may modulate cortical and subcortical synaptic connections (synaptic
plasticity) [2]. Previous studies have reported that tDCS can facilitate motor learning
through synaptic plasticity. This effect is mediated through the induction of nitric oxide
(NO), activation of neurotrophic tyrosine kinase receptor type 2 (TrkB), and expression
of brain-derived neurotrophic factor (BDNF) to promote synaptic plasticity [11,12]. These
molecular mechanisms might underlie the molecular backgrounds for long-term potentia-
tion (LTP) and long-term depression (LTD), and modulate synaptic connections in after
effects. Therefore, due to its safety, application of tDCS to modulate cortical activity has
been increasing in basic and clinical research since 2000 [13–15].
Thus, tDCS is increasingly being applied as a therapy for the motor symptoms of
diverse brain disorders such as Parkinson’s disease (PD). Recently, the front-polar area
(FPA) (Brodmann area 10) has garnered increased attention in motor learning, an important
factor in rehabilitation. This paper aims to review the role of the FPA in motor learning
and to review the current clinical efficacy of tDCS over various brain regions, including the
FPA in PD. Our recent findings in healthy adults show that tDCS over the FPA enhances
motor skill learning through its effects on the motor-related regions [16–20] (see below for
details). We discuss how tDCS over the FPA may facilitate motor skill learning by affecting
the motor-related regions. Consistent with these findings, we will show that tDCS over the
FPA is also effective in PD. Another significant issue in rehabilitation is that a substantial
proportion of patients discontinue rehabilitation programs due to a loss of persistence or
motivation [17–19]. This paper also discusses the neural mechanisms of another effect of
tDCS over the FPA, especially its effect on persistence and motivation. This motivational
aspect is unique to tDCS over the FPA compared to tDCS over the motor-related regions.
These findings suggest that the FPA could be a novel brain region of interest for tDCS in
neuro-rehabilitation.

2. tDCS Effects of the Front-Polar Area (FPA) in Rehabilitation

2.1. A Role of the FPA in Motor Learning and Rehabilitation
Multiple lines of evidence support the notion that the FPA may represent a new thera-
peutic target for tDCS-based rehabilitation, aimed at motor learning. The role played by the
most anterior portion of the prefrontal cortex (PFC) (i.e., FPA) in motor learning is unique
Brain Sci. 2023, 13, x FOR PEER REVIEW 3 of 16

Multiple lines of evidence support the notion that the FPA may represent a new ther-
Brain Sci. 2023, 13, 1604 3 of 15
apeutic target for tDCS-based rehabilitation, aimed at motor learning. The role played by
the most anterior portion of the prefrontal cortex (PFC) (i.e., FPA) in motor learning is
unique in various regards. Some previous noninvasive imaging studies have demon-
in various
strated thatregards.
the FPASome previous
is mainly noninvasive
activated imagingacquire
when subjects studiesnovel
have motor
demonstrated that
task(s) [21–
the FPA is mainly activated when subjects acquire novel motor task(s)
23]. Recently, Kobayashi et al. (2021) examined FPA activity during the acquisition of a [21–23]. Recently,
Kobayashi motor
sequential et al. (2021) examined
task with FPA activity
near-infrared during the(NIRS)
spectroscopy acquisition
[16]. of
Thea sequential motor
study required
task with near-infrared spectroscopy (NIRS) [16]. The study required inexperienced
inexperienced participants to sequentially lay the right hands on a table at a steady pace partici-
pants
of to movements
three sequentially perlay the
sec,right hands
using threeondistinct
a table hand
at a steady pace aoffist
postures: three movements
held vertically,pera
sec, using three distinct hand postures: a fist held vertically, a palm
palm held vertically, and a palm held horizontally [sequential motor (SM) task]. In held vertically, and
thea
palm held
control horizontally
motor task, the [sequential motor (SM)
subjects repeatedly task].the
tapped In the
tablecontrol motorright
with their task,palm
the subjects
at the
repeatedly tapped the table with their right palm at the same speed.
same speed. This control task could be executed without any motor learning. For both This control task
could be executed without any motor learning. For both tasks, the participants
tasks, the participants completed three trials in 30 sec per trial, and performance errors completed
three trials in 30 sec per trial, and performance errors were counted in each trial [16]. The
were counted in each trial [16]. The results indicated that hemodynamic cortical activity
results indicated that hemodynamic cortical activity (Oxy-Hb) was prominent in the PFC,
(Oxy-Hb) was prominent in the PFC, including the FPA and dlPFC, in the first trial, but
including the FPA and dlPFC, in the first trial, but decreased in later trials in the SM task,
decreased in later trials in the SM task, as shown in Figure 1(Aa). No such prominent
as shown in Figure 1(A1). No such prominent responses were observed in the control
responses were observed in the control motor task, as shown in Figure 1(Ab). Cortical
motor task, as shown in Figure 1(A2). Cortical activity changes between the initial (first)
activity changes between the initial (first) and subsequent (second) trials in the sequential
and subsequent (second) trials in the sequential motor task, reflected in Figure 1B, were
motor task, reflected in Figure 1B, were positively correlated with error reduction between
positively correlated with error reduction between the initial and subsequent trials, rep-
the initial and subsequent trials, representing performance improvement by learning.
resenting performance improvement by learning. These findings support the notion that
These findings support the notion that the FPA contributes significantly to motor learning,
the FPA contributes significantly to motor learning, as there is a positive relation between
as there is a positive relation between larger hemodynamic cortical activity changes in the
larger hemodynamic cortical activity changes in the PFC, including the FPA, and a larger
PFC, including the FPA, and a larger performance improvement.
performance improvement.

Figure 1.
Figure Relations between
1. Relations betweenthe thePFC
PFC hemodynamic
hemodynamicactivity
activityininthe
thehand
handmovement
movementtasks tasksand
andtask
task
performance.Reproduced
performance. ReproducedfromfromKobayashi
Kobayashietetal.
al.(2021)
(2021)[16]
[16]under
underaa CC-BY
CC-BY license.
license. Topographical
Topographical
maps
mapsofofthe
thePFC
PFCcortical
corticalactivity
activityshown
shownas
aseffect
effectsizes
sizesin
inthe
thethree
threeconsecutive
consecutivetrials
trialsin
inthe
thesequential
sequential
motor (SM) (A1) and control motor (A2) tasks. NIRS recording channels on the head are shown as
yellow dots. (B) Positive relationships between changes in PFC cortical activity and SM-task error
reduction, which occurred on the first and second trials. The dotted line indicates a regression line.
 motor (SM) (A1) and control motor (A2) tasks. NIRS recording channels on the head are shown as
yellow dots. (B) Positive relationships between changes in PFC cortical activity and SM-task error
reduction, which occurred on the first and second trials. The dotted line indicates a regression line.
Brain Sci. 2023, 13, 1604 4 of 15
These results suggest that the FPA plays a role in motor rehabilitation, where motor
learning plays a crucial part. Ishikuro et al. (2014) examined the function of the FPA in
motor learning in rehabilitation using NIRS [17]. Healthy participants were asked to per-
These results suggest that the FPA plays a role in motor rehabilitation, where motor
form a peg board task for upper-extremity functions in the simple test for evaluating hand
learning plays a crucial part. Ishikuro et al. (2014) examined the function of the FPA
function (STEF): they picked up a peg using their right thumb and index finger and in-
in motor learning in rehabilitation using NIRS [17]. Healthy participants were asked to
serted it ainto
perform pegaboard
hole intaskthe
forSTEFF board. Thefunctions
upper-extremity pegs are in small pins used
the simple for evaluating
test for this activity. In
each of the eight trials, the subjects had to repeat these actions
hand function (STEF): they picked up a peg using their right thumb and index finger as fast as possibleandfor 20
seconds.itItinto
inserted is noteworthy
a hole in thethat STEFFtheboard.
subjects Thewere
pegsrequired
are smallto continuously
pins used for this improve
activity. their
performance over the eight trials, which contrasts with the study
In each of the eight trials, the subjects had to repeat these actions as fast as possible of Kobayashi et al.for
(2021).
Theseconds.
20 results again indicated that
It is noteworthy thatthe
theFPA was highly
subjects active during
were required this task in
to continuously which con-
improve
their
tinuousperformance
performance overimprovement
the eight trials,was which contrasts
required with2).
(Figure theFurthermore,
study of Kobayashi et al.
both behavioral
(2021). The results
performance again i.e.,
(peg score, indicated that the
the number ofFPA
pegswas highlyinto
inserted active
the during
peg holes thisper
task in and
trial)
which continuous performance improvement was required (Figure
cortical activity in the FPA during the peg board task increased incrementally in subse-2.1). Furthermore, both
behavioral
quent trials. performance
To measure (peg
thescore, i.e., the number
incremental speed of of pegs
theseinserted into the peg
two parameters holesthe
across pereight
trial) and cortical activity in the FPA during the peg board task increased incrementally
trials in each subject, both parameters were subjected to simple linear regression analysis.
in subsequent trials. To measure the incremental speed of these two parameters across
“Incremental speed of hemodynamic activity (Oxy-Hb gain)” was assessed by the slope
the eight trials in each subject, both parameters were subjected to simple linear regression
of this fitted line. In the same way, “Incremental speed of behavioral performance (perfor-
analysis. “Incremental speed of hemodynamic activity (Oxy-Hb gain)” was assessed by the
manceofgain)”
slope wasline.
this fitted evaluated by itsway,
In the same slope of the fittedspeed
“Incremental line. ofFigure 3A illustrates
behavioral performance that per-
(performance gain)” was evaluated by its slope of the fitted line. Figure 3A illustrates that that
formance gain is positively associated with Oxy-Hb gain in the FPA. This suggests
the FPA helps
performance gaintoispromote
positively motor learning.
associated with To further
Oxy-Hb gaintest thisFPA.
in the possibility, Ishikuro
This suggests that et al.
(2014)
the FPAapplied
helps toanodal
promote tDCS overlearning.
motor the FPA To before thetest
further pegthis
board task. AsIshikuro
possibility, a result,etthe al.find-
ings demonstrate
(2014) applied anodal that anodal
tDCS over tDCS
the FPA increased
before the peg
pegscores, as shown
board task. in Figure
As a result, 3B. Further-
the findings
demonstrate
more, Oxy-Hb thatgain
anodal tDCS
in the FPA increased peg scores,
was positively as shownwith
associated in Figure
those3B.in Furthermore,
the left premotor
Oxy-Hb gain in the
area (Lt-PMA), leftFPA was positively
primary motor area associated
(Lt-M1),withand those in the left
left primary premotor area area
somatosensory (Lt- (Lt-
PMA), left primary motor area (Lt-M1), and left primary somatosensory
S1). This suggests that the FPA promotes motor learning through its effects over the so- area (Lt-S1). This
suggests
matosensory that the
andFPA promotes motor
motor-related areas.learning through its effects over the somatosensory
and motor-related areas.

Figure 2. Averaged hemodynamic responses during a performance of a peg board task. Reproduced
from Ishikuro et al. (2014) [17] under a CC-BY license. Cortical activity (changes in Oxy-Hb) rapidly
Brain Sci. 2023, 13, x FOR PEER REVIEW 5 of 16
Brain Sci. 2023, 13, 1604 5 of 15

Figure 2. Averaged hemodynamic responses during a performance of a peg board task. Reproduced
increased
from during
Ishikuro the(2014)
et al. task at theunder
[17] FPA and sevenlicense.
a CC-BY somatosensory and motor-related
Cortical activity (changes inareas (supplemen-
Oxy-Hb) rapidly
increased
tary motorduring the task
area (SMA), atpremotor
left the FPA andareaseven somatosensory
(Lt-PMA), and motor-related
right premotor areas
area (Rt-PMA), left (supple-
primary
mentary
motor areamotor area (SMA),
(Lt-M1), left premotor
right primary motorarea (Lt-PMA),
area (Rt-M1),right premotorsomatosensory
left primary area (Rt-PMA), area
left primary
(Lt-S1),
motor areaprimary
and right (Lt-M1),somatosensory
right primary motor area (Rt-M1),
area (Rt-S1)). left in
Changes primary somatosensory
Oxy-Hb, total-Hb, andarea (Lt-S1), con-
deoxy-Hb and
right primary somatosensory area (Rt-S1)). Changes in Oxy-Hb, total-Hb, and deoxy-Hb
centrations are shown by red, green, and blue lines, respectively. Arrows represent the onset of concentra-
tions are shown by red, green, and blue lines, respectively. Arrows represent the onset of the task.
the task.

Figure 3.
Figure FPA role
3. FPA role in
in motor
motor learning
learning in
in aa peg
peg board
board task.
task. Reproduced
Reproduced fromfrom Ishikuro
Ishikuro etet al.
al. (2014)
(2014) [17]
[17]
under a CC-BY license. (A) Positive relations between task performance gain and
under a CC-BY license. (A) Positive relations between task performance gain and FPA Oxy-Hb gain. FPA Oxy-Hb
gain.dotted
The The dotted line indicates
line indicates a regression
a regression line. Each
line. Each filledfilled
symbol symbol indicates
indicates data data for each
for each subject.subject.
(B)
Effects of tDCS
(B) Effects overover
of tDCS the the
FPAFPAon task performance
on task performance(peg(peg
scores) in the
scores) pegpeg
in the board task.
board *, p *,< p0.05.
task. < 0.05.

2.2. Modulatory
2.2. Modulatory Effects
Effects of
of the
the FPA
FPA on
on the
the Motor-Related
Motor-Related Regions
Regions
Previous studies suggest that the primary
Previous studies suggest that the primary motor motor areaarea
(M1 area) is implicated
(M1 area) in skilled
is implicated in
skilled motor learning, where functional reorganization and synaptic plasticity[12,24].
motor learning, where functional reorganization and synaptic plasticity occur occur
Since the FPA projects to the M1 area indirectly by way of other cortical areas including
[12,24]. Since the FPA projects to the M1 area indirectly by way of other cortical areas
the dlPFC [25–27], the FPA might reorganize synaptic connections in the M1 areas to
including the dlPFC [25–27], the FPA might reorganize synaptic connections in the M1
improve motor skills. Previous tDCS studies reported that M1 tDCS reorganized not only
areas to improve motor skills. Previous tDCS studies reported that M1 tDCS reorganized
functional connectivity within the M1 area, but also functional connectivity between the
not only functional connectivity within the M1 area, but also functional connectivity be-
M1 and other cortical areas, and between the M1 and subcortical areas to improve motor
tween the M1 and other cortical areas, and between the M1 and subcortical areas to im-
rehabilitation [28–30]. Therefore, tDCS over the FPA may facilitate the FPA role to improve
prove motor rehabilitation [28–30]. Therefore, tDCS over the FPA may facilitate the FPA
motor learning, partly through induction of reorganization and synaptic plasticity in the
role to improve motor learning, partly through induction of reorganization and synaptic
M1 area. Ota et al. (2020) investigated this possibility by activating the FPA by means of
plasticity in the M1 area. Ota et al. (2020) investigated this possibility by activating the
neurofeedback (NFB) training instead of tDCS [20]. In NFB training, half of the subjects were
FPA by means of neurofeedback (NFB) training instead of tDCS [20]. In NFB training, half
shown hemodynamic cortical activity of their own FPA on a monitor (real NFB training),
of the subjects were shown hemodynamic cortical activity of their own FPA on a monitor
while the remaining subjects were shown randomized false activity (sham NFB training).
(real NFB training),
All subjects receivedwhile
the NFBthe training
remaining forsubjects
6 days, were shown
in which theyrandomized
performed false activity
imagery of a
(sham NFB training). All subjects received the NFB training for 6 days, in which
peg board task to increase FPA activity under the feedback of their own FPA or randomized they per-
formed imagery
false activity. of aand
Before pegafter
board
thetask
NFBtotraining,
increasethe
FPA activity
subjects underNIRS
received the feedback
studies toofassess
their
Brain Sci. 2023, 13, x FOR PEER REVIEW 6 of 16

own FPA or randomized false activity. Before and after the NFB training, the subjects re-
Brain Sci. 2023, 13, 1604 ceived NIRS studies to assess brain hemodynamic activity during the performance of the
6 of 15
peg board task. After the NFB training, the subjects with the real NFB training exhibited
hemodynamic cortical responses in the left somatosensory and motor-related areas in-
cluding the premotor
brain hemodynamic area (PMA),
activity during theM1performance
area, and primary somatosensory
of the peg board task. After cortexthe(S1)
NFB(Fig-
ure 4(A1)),
training, thewhile thewith
subjects subjects with
the real thetraining
NFB sham NFB training
exhibited exhibited hemodynamic
hemodynamic cortical responses cortical
in the left somatosensory
responses and motor-related
in the supplementary motor area areas
(SMA) including
(Figurethe premotor
4(A2)). area (PMA),
Additional M1 in-
analyses
area, and primary somatosensory cortex (S1) (Figure 4(A1)), while
dicated that cortical activity gain in the hand area of the M1 (lateral part of the left Mthe subjects with the
sham NFB
(lateral trainingwhich
Lt-M1)), exhibited
washemodynamic
defined as activitycorticalinresponses
the lateralin the supplementary
Lt-M1 area beforemotor the NFB
training divided by that after the NFB training, was significantly linked togain
area (SMA) (Figure 4(A2)). Additional analyses indicated that cortical activity in the
performance
hand area
gain, of the
defined asM1
peg(lateral
scorespart of the
before theleft M (lateral
training Lt-M1)),
divided bywhich
those was
afterdefined as activity
the training (Figure
in the lateral Lt-M1 area before the NFB training divided by that after the NFB training,
4(B1)). Furthermore, cortical activity in the left somatosensory and motor-related areas
was significantly linked to performance gain, defined as peg scores before the training
during the performance of the peg board task after the NFB training was significantly and
divided by those after the training (Figure 4(B1)). Furthermore, cortical activity in the
positively linked to cortical activity in the FPA during the performance of the imagery on
left somatosensory and motor-related areas during the performance of the peg board task
the
after the NFBof
last day the NFB
training wastraining (Figure
significantly and4(B2)).
positivelyThese results
linked suggest
to cortical that in
activity thetheFPAFPAreor-
ganizes
during thesynaptic connectivity
performance patterns on
of the imagery in the
the M1last area,
day of sothe
that reorganized
NFB activity
training (Figure patterns
4(B2)).
of M1 neurons in the M1 area are more suitable for the peg board
These results suggest that the FPA reorganizes synaptic connectivity patterns in the M1 task [20]. Interestingly,
in thesosubjects
area, with the sham
that reorganized NFB
activity training,
patterns of M1 cortical
neurons activity
in the in
M1the SMA
area increased
are more during
suitable
the performance
for the peg boardoftask the[20].
peg board task after
Interestingly, the subjects
in the trainingwith(see the
above).
shamThe NFBSMA has been
training,
proposed to function
cortical activity as “anincreased
in the SMA action monitoring
during the system”
performance that of
provides
the peg warning
board task signals
after for
the training
errors (see above).
and incorrect The SMA
responses hasInbeen
[31]. proposed
the sham NFBtotraining,
functiontheas “an action monitoring
participants were shown
system” that
randomly provides warning
generated feedbacksignals
signals forthat
errors
were andirrelevant
incorrect responses
to performing[31]. Inthethepeg
sham board
NFB training, the participants were shown randomly generated
task, suggesting that the FPA could lead to erroneous reorganization of the synapticfeedback signals that werecon-
irrelevant patterns
nectivity to performingin thetheM1pegarea
board task, suggesting
during the sham NFB that the FPA could
training. Theseleadfindings
to erroneoussuggest
reorganization of the synaptic connectivity patterns in the M1 area
the SMA activity after the sham NFB training is involved in detection of erroneous syn- during the sham NFB
training. These findings suggest the SMA activity after the sham NFB training is involved
aptic activity in the somatosensory and motor-related areas, which may promote refor-
in detection of erroneous synaptic activity in the somatosensory and motor-related areas,
mation of correct (new) association between incoming sensory inputs and motor re-
which may promote reformation of correct (new) association between incoming sensory
sponses.
inputs and motor responses.

Figure 4. FPA role in improving performance in neurofeedback (NFB) training for six days. Reproduced
from Ota et al. (2020) [20] under a CC-BY license. (A) Averaged task-related responses, shown as NIRS-SPM
Brain Sci. 2023, 13, 1604 7 of 15

T-statistic maps, during a performance of a peg board task after the real (A1) and sham (A2) neuro-
feedback (NFB) training. The real NFB training induced cortical activation in the somatosensory and
motor-related areas (A1), while the sham NFB training induced SMA activation (A2). (B) Relation-
ships between Oxy-Hb gain in the hand area of the left primary motor cortex (lateral Lt-M1) and
performance gain in the peg board task (B1), and those between cortical activity in the FPA during
the performance of the real NFB training on the 6th day of the training, and cortical activity in the
somatosensory and motor-related areas during performance of the peg board task after the real NFB
training (B2). The dotted lines indicate regression lines. The data in each circle indicate data from
each subject.

3. Parkinson’s Disease (PD)

3.1. Effects of tDCS over the M1, Dorsolateral PFC (dlPFC), and Cerebellum
This section briefly describes the current status of tDCS in PD. The main symptoms
in PD include motor symptoms (tremors at rest, rigidity, bradykinesia, freezing of gait,
and impaired postural reflexes). PD also exhibits nonmotor symptoms (e.g., cognitive
deficits, depression, orthostatic hypotension, REM sleep abnormalities, etc.) that tend
to appear before the motor symptoms occur [32]. Anatomically, PD is characterized by
gradual depletion and degeneration of dopamine neurons, especially in the midbrain
substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), resulting in
network dysfunction of cortico-basal ganglia circuits (dysfunction of the direct and indirect
pathway system) [33–35]. Furthermore, cortical network disruption may be involved in PD
symptoms. Tessitore et al. (2012) reported that severity of freezing of gait was associated
with a reduction of functional connectivity within the two cortical networks: executive-
attention (PFC) and visual (right occipito-temporal gyrus) networks [36]. In addition,
executive function, which is mainly supported by the dlPFC, is positively associated with
hand dexterity [37–39]. These findings suggest that the target brain areas for PD treatment
should include not only the cortico-basal ganglia motor circuits, but also cortical circuits
such as the dlPFC.
Deep brain stimulation (DBS) is a recognized surgical intervention for the treatment of
PD that can inhibit (ameliorate) overactivity of the subthalamic nucleus (STN) or internal
segment of globus pallidus (GPi), while regenerative therapy is attracting attention as a
state-of-the-art treatment aiming for a radical cure. Nevertheless, these therapies are not
readily accessible, and drug therapy remains the most common and essential treatment
for PD. Furthermore, long-term use of medication often results in side effects such as
wearing-off and dyskinesia. In light of the issues in drug therapy, neuro-rehabilitation
using NIBS has recently garnered attention in the context of PD [40–46].
In clinical studies of tDCS in PD patients, two stimulation sites are often used as
regions of interest (ROI): the M1 and dlPFC. The tDCS studies in PD reported that an-
odal stimulation of the M1 improved motor symptoms [43,44] (Supplementary Table S1),
while anodal stimulation of the dlPFC improved executive and cognitive functions [45,46]
(Supplementary Table S1). Although the sample size was small, many new reports on PD
suggest that tDCS treatment is effective. However, the neural mechanism of improvement
is not yet fully clarified, and further accelerated research is necessary. Moreover, it may not
be the best treatment to solely stimulate motor-related areas to improve motor function
in PD. To develop stimulation sites for tDCS, it is essential to actively use functional MRI
and other techniques to assess after-effects of tDCS to induce functional changes in the
stimulated areas.
The neural network connecting the cerebellum and the basal ganglia [47] is gaining
more clarity, as are the projections from the cerebellum (dentate nucleus) to the PFC and
other areas via the thalamus [48]. This has led to increased interest in the relationship
between PD and the cerebellum. Furthermore, research suggests that activities in the
cerebellum and PFC, including the FPA, are functionally linked in humans [49]. Based
on the findings, researchers suggest that applying tDCS to the cerebellum during motor
practice could enhance motor skills in PD. de Albuquerque et al. [50,51] investigated the
Brain Sci. 2023, 13, 1604 8 of 15

impact of anodal cerebellar tDCS (c-tDCS) on the upper extremity function of PD patients
while they learned to perform a complex optokinetic isometric precision grip strength task
(PGT). They found that applying c-tDCS to the cerebellum did not result in a significant
improvement in motor skill acquisition for hand and arm tasks [50,51]. While there is
no current evidence to suggest an improvement in upper limb function, Workman et al.
conducted a study on cerebellar functions such as “balance and walking ability”. Their
findings showed significantly higher Berg Balance Scale scores with the application of
high-intensity cerebellum stimulation (4.0 mA × 20 min) [52]. These findings suggest that
c-tDCS may require a higher current intensity due to the cerebellum being covered by a
relatively thick occipital bone, or anatomical/physiological properties of the cerebellum
different from the cortex.

3.2. Effects of tDCS over the FPA in PD Patients

The previous sections suggest that tDCS over the M1 area or dlPFC improves motor or
nonmotor symptoms in PD, and that tDCS over the FPA promotes motor learning through
reorganization of M1 activity in healthy people, further suggesting that tDCS over the FPA
may ameliorate PD symptoms. Ishikuro et al. [18] investigated effects of tDCS (anodal,
cathodal, and sham tDCS) over the FPA on motor and nonmotor symptoms in a cross-over
design in PD patients [18] (Supplementary Table S1). They reported that anodal tDCS
significantly reduced normalized scores of motor disability in the Unified PD Rating Scale
(UPDRS (part III)) (Figure 5(A1)), and significantly raised scores of motor functions in
the Fugl Meyer Assessment set (FMA), while it significantly reduced time to complete a
high dexterity task in STEF [18]. The same anodal tDCS also improved nonmotor function:
reduction of normalized time required to complete the Trail Making Test A (TMT-A) to
assess attention/executive functions (Figure 5(A2)). Thus, the tDCS of the FPA ameliorated
not only motor, but also nonmotor symptoms in PD.
Dopamine neurons in the SNc and VTA receive glutamate transmissions directly or
indirectly from the PFC [53–56]. Additionally, dopamine neuron activity is functionally
associated with PFC neuron activity [57,58], and tDCS of the PFC can substantially raise
dopamine and tyrosine levels in PD model mice [59]. Therefore, it is plausible to assume that
FPA stimulation, which likely sends excitatory projections to midbrain dopamine neurons
or activates the dlPFC projecting to dopamine neurons, could impact dopamine cells in
the SNc of individuals with PD. It is also possible that tDCS over the FPA could enhance
brain regions linked to neuromelanin (refer to below). Neuromelanin is a brown pigment
that accumulates in neurons containing catecholamines, and is abundant in dopaminergic
cells in the SNc and noradrenergic cells in the locus coeruleus (LC). Recently, fMRI studies
reported interesting findings that neuromelanin is closely associated with clinical symptoms
of PD assessed using UPDRS-III [60,61]. Neuromelanin can be relatively easily imaged
by T1-weighted 3T-MRI [62,63]. Ishikuro et al. (2021) examined effects of tDCS over the
FPA in one PD patient as a case report, using noninvasive imaging of neuromelanin to
reveal dopamine neurons [19]. They reported that the same tDCS protocol (i.e., 2 weeks of
rehabilitation with tDCS in the FPA) increased the neuromelanin-sensitive area in the SNc,
where dopamine neurons are located, from 43.2 to 53.2 mm2 (increases by 18.8%), and that
the patient exhibits clinically meaningful improvement of motor deficits (Figure 5B). The
PFC provides direct or indirect excitatory signals with dopamine neurons (as discussed
previously). The survival of dopamine neurons or expression of a dopaminergic phenotype
is activity-dependent [64,65]: a decline in electrical activity in dopamine neurons results in
cellular death or a reduction of tyrosine hydroxylase (which is the rate-limiting enzyme
for dopamine synthesis). Consequently, tDCS over the FPA might support the survival of
dopamine neurons and promote the expression of tyrosine hydroxylase, possibly resulting
in increases in the area sensitive to neuromelanin imaging. Furthermore, anodal tDCS
of the frontal cortex for 3 weeks raised dopamine content of the entire brain in a mouse
PD model [59]. Since dopamine is crucial for executive functions in the PFC [66,67], these
findings indicate that tDCS over the FPA, combined with physical rehabilitation, might
Brain Sci. 2023, 13, x FOR PEER REVIEW 9 of 16

Brain Sci. 2023, 13, 1604 content of the entire brain in a mouse PD model [59]. Since dopamine is crucial for execu-
9 of 15
tive functions in the PFC [66,67], these findings indicate that tDCS over the FPA, combined
with physical rehabilitation, might cause plastic changes in the dopamine neurons of PD
patients, resulting in an improvement of both motor and nonmotor symptoms (e.g., defi-
cause plastic changes in the dopamine neurons of PD patients, resulting in an improvement
cits in executive functions).
of both motor and nonmotor symptoms (e.g., deficits in executive functions).

Figure 5. Effects of tDCS over the FPA on PD symptoms (A) (reproduced from Ishikuro et al., 2018
Figure 5. Effects of tDCS over the FPA on PD symptoms (A) (reproduced from Ishikuro et al.,
[15] under a CC-BY license) and neuromelanin (NM) imaging in the midbrain (B) (created from the
2018 [15] under a CC-BY license) and neuromelanin (NM) imaging in the midbrain (B) (created
original NM-MRI data by Ishikuro et al., 2021 [19]). (A) Effects of the tDCS on motor disturbance
fromand
(A1) thenonmotor
original NM-MRI
functionsdata by Ishikuro et al.,
(attention/executive 2021 [19]).
functions) (A2).(A) Effects
Motor of the tDCS
disability on motor
was evaluated
disturbance (A1) and nonmotor functions (attention/executive functions) (A2). Motor
with the Unified PD Rating Scale (UPDRS (part III: motor examination)) after intervention of each disability was
evaluated
tDCS with the
stimulation Unifiedcathodal,
(anodal, PD Rating Scale
and sham(UPDRS
tDCS).(part III: motor
Nonmotor examination))
functions after intervention
were assessed with the
Trail
of each tDCSTest
Making A (TMT-A).
stimulation ∗, p cathodal,
(anodal, < 0.05. (B)and
Imaging
sham of dopamine
tDCS). Nonmotorneurons by neuromelanin
functions were assessed mag-
with
netic resonance imaging (NM-MRI) in the substantia nigra compacta (SNc) before
the Trail Making Test A (TMT-A). ∗, p < 0.05. (B) Imaging of dopamine neurons by neuromelanin (B1) and after
(B2) FPA tDCS
magnetic in oneimaging
resonance PD patient. Red pixels
(NM-MRI) in theindicate NM-sensitive
substantia areas(SNc)
nigra compacta in thebefore
SNc, where dopa-
(B1) and after
mine neurons are located.
(B2) FPA tDCS in one PD patient. Red pixels indicate NM-sensitive areas in the SNc, where dopamine
neurons are located.
4. Neural Mechanisms of Effects of FPA tDCS
4. Neural Mechanisms
The previous of indicate
sections Effects of FPA
that tDCStDCS of the FPA, which raises the excita-
anodal
bility The
of pyramidal
previous neurons
sections in the FPA,
indicate thatmay facilitate
anodal tDCSorofimprove
the FPA,motorwhich and nonmotor
raises the ex-
citability of pyramidal neurons in the FPA, may facilitate or improve
functions in healthy subjects and PD patients. Multiple mechanisms may be responsible motor and nonmotor
functions
for in healthy
these effects subjects
(Figure and tDCS
6). First, PD patients.
over theMultiple
FPA may mechanisms
reorganize maythebe responsible
functional for
con-
these effects
nectivity (Figure
of the 6). First,
M1 area tDCS over
to improve motorthe FPA may reorganize
learning, as shown in thethe
functional
study withconnectivity
NFB to
of the M1
activate thearea
FPA.toThe
improve motor learning,
FPA projects as shown
to the dlPFC in the controls
[26], which study with theNFB to activate
excitability the
of the
FPA. The FPA
ipsilateral projects
M1 area [25].toFurthermore,
the dlPFC [26],the which
FPAcontrols
and M1the areaexcitability of the ipsilateral
are functionally connected M1
area [25]. Furthermore, the FPA and M1 area are functionally connected
[68]. These findings suggest that tDCS over the FPA might reorganize the functional con- [68]. These findings
suggest that
nectivity tDCS
of the over through
M1 area the FPA might reorganize thesynaptic
activity-dependent functional connectivity
plasticity of theSecond,
(e.g., LTP). M1 area
through activity-dependent synaptic plasticity (e.g., LTP). Second, tDCS
tDCS over the FPA might facilitate nonmotor cognitive functions (e.g., executive function) over the FPA might
facilitateFPA
through nonmotor cognitive
projections to thefunctions (e.g., executive
dlPFC. Consistently, function) through
a meta-analysis studyFPA projections
reported that
to the
the FPA dlPFC. Consistently,
coactivates with the a meta-analysis
dlPFC (areas study
9/46)reported that the
in various FPAincluding
tasks coactivatesworking
with the
dlPFC (areas 9/46) in various tasks including working memory tasks [69]. Furthermore,
the lateral FPA is believed to have a crucial role in executive function and stimulus-oriented
action [70,71]. Third, tDCS over the FPA might exert its effects by acting on dopamine
 Brain Sci. 2023, 13, x FOR PEER REVIEW 10 of 16

memory tasks [69]. Furthermore, the lateral FPA is believed to have a crucial role in exec-
utive function and stimulus-oriented action [70,71]. Third, tDCS over the FPA might exert
Brain Sci. 2023, 13, 1604 10 of 15
its effects by acting on dopamine neurons. Midbrain dopamine neurons receive direct
and/or indirect glutamatergic excitatory afferents from the PFC [53–56], and activity of
dopamine neurons correlates to that of PFC neurons [57,58], suggesting that elevated FPA
neurons.
activity by Midbrain
tDCS may dopamine
promoteneurons
dopamine receive
releasedirect
in the and/or indirect glutamatergic
somatosensory and motor-relatedex-
citatory
areas, as afferents
well asfrom the PFC
the basal [53–56],
ganglia. Sinceanddopamine
activity offacilitates
dopamine LTPneurons
inductioncorrelates
as welltoas
that of PFC
motor skillneurons
learning[57,58],
[72–74],suggesting that elevated
increased dopamine FPAin
release activity by tDCS mayand
the somatosensory promote
motor-
dopamine release in the somatosensory and motor-related areas, as
related areas may facilitate the first mechanism in synaptic plasticity. In the case of well as the basal gan-
PD,
glia. Since dopamine facilitates LTP induction as well as motor
increases in NM-sensitive areas, where dopaminergic neurons are located, by tDCS may skill learning [72–74],
increased dopamine release
increase dopamine release inin the
thecortico-basal
somatosensory and motor-related
ganglia circuits as wellareas
as in may facilitate
the PFC, which
the first mechanism in synaptic plasticity. In the case of PD, increases in
contributes to the amelioration of PD symptoms (see above section). Fourth, elevated FPA NM-sensitive areas,
where dopaminergic
activity by tDCS could neurons
enhance are one’s
located, by tDCS may
motivational increase
drive dopamine
and facilitate the release
processinofthe
mo-
cortico-basal ganglia circuits as well as in the PFC, which contributes to
tor learning. Hosoda et al. [75] showed the crucial role of the FPA in persistence during the amelioration of
PD symptoms (see above section). Fourth, elevated FPA activity by
difficult motor learning, whereas Soutschek et al. [76] found that tDCS over the FPA en- tDCS could enhance
one’s motivational drive and facilitate the process of motor learning. Hosoda et al. [75]
hances motivation for cognitive and physical efforts. These motivational changes associ-
showed the crucial role of the FPA in persistence during difficult motor learning, whereas
ated with the FPA are critical in physical rehabilitation, since a significant number of pa-
Soutschek et al. [76] found that tDCS over the FPA enhances motivation for cognitive
tients drop out of rehabilitation programs [77–79], and patients with PD have difficulties
and physical efforts. These motivational changes associated with the FPA are critical in
with mental persistence [80]. The role of the FPA in persistence may be attributed to its
physical rehabilitation, since a significant number of patients drop out of rehabilitation
projection to the nucleus accumbens. Previous neuropsychological studies reported that
programs [77–79], and patients with PD have difficulties with mental persistence [80]. The
deficits in motivation are associated with deficits in goal-directed behaviors in depression
role of the FPA in persistence may be attributed to its projection to the nucleus accumbens.
[81], reminiscent of dropping out of physical rehabilitation, and functional connectivity
Previous neuropsychological studies reported that deficits in motivation are associated
between the FPA and nucleus accumbens is more decreased in patients with more severe
with deficits in goal-directed behaviors in depression [81], reminiscent of dropping out
symptoms in depression [82], while dopamine depletion in nucleus accumbens decreased
of physical rehabilitation, and functional connectivity between the FPA and nucleus ac-
the preference for a high-effort option with high reward [83,84]. Furthermore, manual
cumbens is more decreased in patients with more severe symptoms in depression [82],
dexterity
while dopaminewas disturbed
depletionin inpatients
nucleus with depression
accumbens [85], while
decreased activity offor
the preference nucleus accum-
a high-effort
bens was
option withincreased
high reward during a manual
[83,84]. task in manual
Furthermore, subjectsdexterity
with spinal
waslesions
disturbedcompared with
in patients
intact subjects. Additionally, functional connectivity between the
with depression [85], while activity of nucleus accumbens was increased during a manualnucleus accumbens and
M1 area was increased during relearning of a hand motor task after spinal
task in subjects with spinal lesions compared with intact subjects. Additionally, functional lesions in mon-
keys [86]. The
connectivity findings
between suggest accumbens
the nucleus that the neural
and M1circuits comprising
area was increased theduring
FPA, relearning
nucleus ac-
cumbens, and dopaminergic neurons may promote both effortful
of a hand motor task after spinal lesions in monkeys [86]. The findings suggest that thelearning of manual mo-
tor tasks
neural and preservation
circuits comprising the of meticulous
FPA, nucleus manual dexterity.
accumbens, andIn summary, theneurons
dopaminergic neural mech-
may
anisms impacted by tDCS over the FPA in motor learning are
promote both effortful learning of manual motor tasks and preservation of meticulouscomplex and involve mul-
tiple processes that contribute to improvement of fine manual
manual dexterity. In summary, the neural mechanisms impacted by tDCS over the FPA indexterity, which may facil-
itate rehabilitation.
motor learning are complex and involve multiple processes that contribute to improvement
of fine manual dexterity, which may facilitate rehabilitation.

Figure 6. Hypothetical neural mechanisms of tDCS over the FPA in neuro-rehabilitation. Dopamine
neurons in the SNc and VTA receive excitatory glutamatergic transmission directly and/or indirectly
from the PFC. Thus, tDCS stimulation of FPA, which sends projections to midbrain dopamine neurons,
may affect dopamine cells in the SNc of PD patients. Furthermore, tDCS over the FPA might reorganize
Brain Sci. 2023, 13, 1604 11 of 15

the functional connectivity of the M1 area through the dlPFC and nucleus accumbens (NAC).
Red arrows indicate direct and/or indirect projections from the FPA, while blue arrows indicate
dopamine projections.

5. Future Issues on tDCS over the FPA

We have reviewed the efficacy of tDCS over the FPA, which suggests that this tech-
nique might be useful in clinical applications, not only in healthy subjects, but also in PD.
However, upcoming challenges pertaining to tDCS over the FPA need to be addressed.
First, optimal conditions for tDCS over the FPA (current intensity, duration, location, etc.)
should be determined. Inconsistency of clinical efficacy of tDCS among studies may be
ascribed to different stimulation protocols [87]. Recently, high-definition tDCS (HD-tDCS)
has been introduced, which allows more focused current delivery [88]. HD-tDCS should be
applied to the FPA for more focused stimulation to better understand roles of the FPA in
rehabilitation. Second, only a small sample of patients with PD were tested with tDCS over
the FPA in the previous studies [15,16]. Further studies in larger populations are needed
to determine clinical efficacy of tDCS over the FPA. Third, although applying FPA tDCS
improved both motor and nonmotor functions of PD patients, further studies are needed
to clarify the time-lapse of improvements during repeated interventions, as well as the
time-lapse of changes in those improvements after repeated interventions. Fourth, there are
multiple forms of motor learning including use-dependent motor learning (repetitive motor
learning), instructive motor learning (strategy-based motor learning), reinforcement motor
learning, and sensorimotor adaptation-based motor learning [89]. Although repetitive
motor learning is supposed to play a major role in rehabilitation, these multiple forms of
motor learning could occur independently and simultaneously [89]. Furthermore, these
multiple forms of motor learning could interact with each other [90]. Further research
is needed to clarify how the tDCS over the FPA modulates each form of motor learn-
ing, and how it modulates the interactions between various learning mechanisms during
physical rehabilitation.

6. Conclusions
Emerging evidence suggests that tDCS can safely modulate neuronal excitability by
producing either somatic depolarization (anodal stimulation) or somatic hyperpolarization
(cathodal stimulation), based on the polarity of a weak current from the scalp. This
technology has become increasingly popular in the field of rehabilitation medicine for
treating neurodegenerative illnesses, such as PD.
Previous studies have primarily applied tDCS to the M1 region in PD patients, and
have reported the usefulness of tDCS in neuro-rehabilitation. Recent neuropsychological
and clinical studies have reported that tDCS of the FPA can improve motor learning and
motor functions in both healthy participants and patients with PD. tDCS over the FPA may
promote motor skill learning through its effects on the M1 area and/or midbrain dopamine
neurons. Furthermore, recent studies have revealed additional distinctive effects of tDCS
of the FPA, including impacts on persistence and motivation, which are important for
rehabilitation. These results suggest that the FPA could be a new target for the application
of tDCS in neuro-rehabilitation.

Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/brainsci13111604/s1, Table S1: Summary of tDCS studies in
patients with PD.
Author Contributions: Conceptualization, K.I., N.H. and H.N.; writing—original draft preparation,
K.I. and H.N.; writing—review and editing, N.H., H.O., K.F., T.N., K.M., T.S., K.N., S.K. and Y.N.;
funding acquisition, K.I. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by JSPS KAKENHI Grant Number 22K11390, provided from
the JSPS.
Brain Sci. 2023, 13, 1604 12 of 15

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request to the corre-
sponding author. The data are not publicly available due to privacy of the patients.
Conflicts of Interest: The authors declare no conflict of interest.

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