Molecular Psychiatry www.nature.

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ARTICLE
A systematic review and meta-analysis of transcranial direct-
current stimulation effects on cognitive function in patients
with Alzheimer’s disease
1 1✉
Alireza Majdi , Luuk van Boekholdt1, Saeed Sadigh-Eteghad2 and Myles Mc Laughlin

© The Author(s), under exclusive licence to Springer Nature Limited 2022

Transcranial direct-current stimulation (tDCS) appears to enhance cognitive function in Alzheimer’s disease (AD). Accordingly, over
the last two decades, the number of studies using tDCS for AD has grown. This study aimed to provide a quantitative assessment of
the efficacy of tDCS in improving cognitive function in patients with AD. We systematically searched the literature until May 2021 to
identify relevant publications for inclusion in our systematic review and meta-analysis. Eligible studies were sham-controlled trials
assessing the impacts of anodal or cathodal tDCS on cognitive function in patients with AD. The outcome measure of this study was
the effects of tDCS on distinct cognitive domains including memory, attention, and global cognitive function. The initial search
yielded a total of 323 records. Five other articles were found using manual search of the databases. Of these, 13 publications (14
1234567890();,:

different studies) with a total of 211 patients of various degrees of AD severity underwent meta-analysis. Meta-analysis revealed the
non-significant effects of tDCS on attention (0.425 SMD, 95% CI, −0.254 to 1.104, p = 0.220), and significant positive impacts on the
amelioration of general cognitive measures (1.640 SMD, 95% CI, 0.782 to 2.498, p < 0.000), and memory (1.031 SMD, 95% CI, 0.688 to
1.373, p < 0.000) dysfunction in patients with AD. However, the heterogeneity of the studies were high in all subdomains of
cognition (ϰ2 = 22.810, T2 = 0.552, d.f. = 5, I2 = 78.80%, p < 0.000 for attention, ϰ2 = 96.29, T2 = 1.727, d.f. = 10, I2 = 89.61%, p <
0.000 for general cognition, and ϰ2 = 7.253, T2 = 0.085, d.f. = 5, I2 = 31.06%, p = 0.203 for memory). Improved memory and general
cognitive function in patients with AD was shown in this meta-analysis. However, due to the small number of studies and the high
heterogeneity of the data, more high-quality studies using standardized parameters and measures are needed before tDCS can be
considered as a treatment for AD.

Molecular Psychiatry; https://doi.org/10.1038/s41380-022-01444-7

INTRODUCTION tDCS delivers a weak electric current, typically ranging between 1

Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder and is the most common cause of dementia in the
elderly. A total of 35.6 million adults were reported to suffer from
AD or AD-like dementia in the world in 2010. Currently, ~44
million people worldwide are living with AD or a related form of
dementia and the number is projected to reach 65.7 million by
2030 [1, 2]. Current practice recommends the use of N-methyl-D-
aspartate (NMDA) receptor partial antagonist, memantine and
cholinesterase inhibitors as the main treatments in patients with
varying degrees of AD. Nevertheless, these agents are shown to
impose adverse effects on the patients and their efficacy is limited
[3]. Because no definite strategy has been established to treat
most types of dementia especially AD, there is an urgent need for
alternative treatments.
Transcranial direct-current stimulation (tDCS), as a noninvasive
neuromodulation method, is safe, tolerable, painless, cost-
effective, and relatively easy to use [4]. Also, another advantage
of tDCS is that it can be done at home which makes it possible to
reach a much wider patient population [5]. Thus, the use of tDCS
has recently gained considerable clinical and academic attention.
and 2 mA, via two or more electrodes positioned on the scalp. This
current passes through the scalp, skull and cerebral-spinal fluid to
create a weak electric field in the brain [6]. This weak electric field
in the brain was until recently the presumed mechanism of action,
with anodal tDCS causing depolarization of the neural membrane
and cathodal tDCS causing hyperpolarization [7]. However, more
recent evidence suggests that tDCS effects on memory may be
caused by stimulating cranial and cervical nerves in the scalp
which then give input to the brain and cause the neuromodu-
latory effect [4, 8, 9].
Recently, a number of clinical trials have shown that tDCS may
improve specific cognitive function in patients suffering from AD
[10, 11]. It has been found that single or repeated administration
of tDCS to the left dorsolateral prefrontal cortex (DLPFC), or the
bilateral temporoparietal regions improves cognitive function in
patients with AD [12, 13]. Along with these results two meta-
analyses have found that anodal tDCS applied over the inferior
frontal cortex, inferior frontal gyrus or DLPFC improves cognitive
function in healthy adults especially when a high current strength
and density were administered [14, 15]. Also, it has been shown

1
Exp ORL, Department of Neuroscience, Leuven Brain Institute, KU Leuven, Leuven, Belgium. 2Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
✉email: Myles.mclaughlin@kuleuven.be

Received: 26 May 2021 Revised: 16 December 2021 Accepted: 11 January 2022

 A. Majdi et al.
2
that older adults have greater cognitive gains than their young
counterparts from tDCS [16]. This is especially important in
patients with AD, as they tend to be old (sporadic AD) rather than
young. This may be explained by the assumption that older
patients have poorer cognitive function leaving a greater room for
improvement during tDCS [17].
However, these findings are not universal and opposing
evidence indicates that repeated application of tDCS to the left
temporal cortex has not been able to improve cognitive abilities in
these patients [18]. In line with that, a meta-analysis showed only
limited effects of multi-session tDCS on cognition in patients with
dementia and mild cognitive impairment (MCI) [19].
Systematic reviews and meta-analysis are thought to deliver an
unbiased summary of existing studies and help understand
discrepancies between the results of preclinical and clinical trials
[20]. There have been two meta-analyses assessing the effects of tDCS
on dementia. However, these data are mixed based on patients with
both AD and other types of dementia such as frontotemporal
dementia and do not focus on AD [19, 21]. Here, we perform a
systematic review and meta-analysis to appraise the effects of tDCS
on cognitive function in patients with varying degrees of AD.
METHODS
The current meta-analysis was conducted using the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22].
Search strategy and eligibility criteria
Two investigators (AM and SSE) independently searched MEDLINE via
PubMed, SCOPUS, and Web of Science for the articles whose title and
abstract included the following keywords: (a) transcranial direct-current
stimulation, tDCS, transcranial electrical stimulation, tES, (b) cognition,
memory, attention, learning and (c) AD, and dementia. Full-text English
studies of case-control type or randomized controlled trials available as of
May 2021 were selected and evaluated. Additional articles were selected
by scanning reference lists for involved studies and earlier (systematic)
reviews, and manual search of Google Scholar. In case of any
inconsistencies between the two investigators, a senior researcher (MML)
judged the articles against inclusion and exclusion criteria and approve the
final list of articles.
The eligibility criteria were as follows: all full-text English case-control or
clinical trial studies performing tDCS on human beings diagnosed with AD
according to the Diagnostic and Statistical Manual of Mental Disorders 5th
Edition (DSM V), the National Institute of Neurological and Communicative
Disorders and Stroke and the Alzheimer’s Disease and Related Disorders
Association (NINCDS-ADRDA) [23], or the International Classification of
Diseases (ICD-10) categorization of mental and behavioral disorders with
no age and gender limits. Single or multi-session anodal or cathodal tDCS
over specific cortical areas was considered as the intervention type, while
single or multi-session sham tDCS over the same cortical regions was
defined as the control condition. Any changes in global cognition or in any
of the cognitive domains from baseline to a postintervention point, as
measured by objective (and not subjective) cognitive scales were
considered as cognition-related neurobehavioral outcomes. In vivo,
in vitro (primary culture or cell line), and ex vivo studies and those using
interventions other than tDCS or patients other than AD such as MCI and
frontotemporal dementia were excluded from this study.
Data extraction
The author, publication year, stimulation type and characteristics (includ-
ing electrode location, current intensity, electrode size, stimulation time,
and number of sessions), neurobehavioral outcomes (mean outcome and
standard deviation (SD) or standard error of mean (SEM)), study quality
assessment, and the reporting of measures to diminish the risk of bias
were extracted from the studies. The time of outcome assessment was not
recorded. When the mean and SD or SEM were not presented in the text,
the primary authors were asked for additional information on these
variables. If the authors were not responsive these values or graphically-
presented data were measured from graphs using Universal Desktop Ruler,
version 2.9. In case of the failure of either of the measures the article was
excluded. When a single study reported more than one experiment, the
data were evaluated as independent experiments. If neurobehavioral
outcomes were reported more than once in the same participants only
data for the last evaluation were recorded. Anodal and cathodal tDCS
sessions were treated as separated experiments in the same study.
Risk of bias assessment in individual studies
The guidelines of Cochrane and its tool [24] were used to assess the risk of
bias. Various aspects, i.e., allocation concealment, blinding of participants
and outcomes, incomplete or selective reporting, and random sequence
generation were evaluated by 2 independent authors (AM and SSE) using
the mentioned resources. A senior author judged any disagreements
between the 2 reviewers. For each element, risk of bias was measured as
low, unclear, or high [25].
Statistical analyses
All data were expressed as mean ± SD. The Comprehensive Meta-Analysis
Software (CMA) software version 2.0 was used to analyze the data. Meta-
analysis was conducted if three or more studies evaluated a comparable
intervention via the random-effects model, as their heterogeneity was
rather high (I2 > 50%) [26]. The standardized mean difference (SMD) was
applied to compare the means of the groups (placebo or sham vs. tDCS) in
each publication. Heterogeneity of the data was measured using the I2
statistic, and 25%, 50%, or 75%, were considered as low, modest, and high,
respectively. Publication bias was not calculated using funnel plots and
trim and fill analyses as funnel plots of the SMD plotted against the
standard error (SE) are vulnerable to misrepresentation, resulting in the
overestimation of the existence and extent of publication bias [27].
If a publication reported data on more than one outcome, conducted on
the same participants, we computed a combined effect across outcomes
while simultaneously avoiding bias [28]. The mean for multiple outcomes
reported for a single subdomain was calculated as,
1 Xm 
Y ¼ Yj (1)
m j
where “m” stands for the number of means, and “Y” is the mean for effect
sizes from different outcomes. However, we estimated the cumulative
variance of these means as,
 2 X   2 X X  pffiffiffiffipffiffiffiffiffi
1 m 1 m
VY ¼ var Yi ¼ Vi þ rjk Vj Vk
m j ¼ 1 m j ¼ 1 j≠k
(2)
where ‘V’ represents variance, “m” is the number of variances in the
formula. In all analyses, p < 0.05 was considered statistically significant.
RESULTS
General study characteristics
The initial search yielded a total of 323 records in PubMed and
SCOPUS. Other articles were found using a manual search of
Google Scholar [29] and ResearchGate [30]. Also, the data
emerging from three other records were obtained from the
authors of the manuscripts [18, 31, 32]. When we restricted our
search to English articles and humans, 49 articles were excluded
and 279 publications remained. Restriction of our findings to
“journal” as the source type and “research article” as the article
type excluded 118 publications leaving 161 articles on hand.
Manual assessment of the title, abstract and keywords (using the
criteria mentioned in methods) excluded 143 articles and yielded
18 articles for the systematic review. Of these, five studies were
case reports and were not included in the meta-analysis. Thirteen
publications were original research articles and five were case
reports. These 13 original research articles (14 different studies)
then underwent meta-analysis (Fig. 1).
General study characteristics are presented in Table 1. A total of
211 patients with various degrees of AD were included in this
meta-analysis. These patients would be treated with various anti-
dementia medications that were continued during the studies.
Thus, tDCS was used as an add-on treatment. Temporal and
dorsolateral prefrontal (DLPFC) (12/14) followed by temporopar-
ietal and frontotemporal cortices (2/14) were the most common
Molecular Psychiatry

Fig. 1 PRISMA flow diagram. Literature selection summary based on the PRISMA guidelines depicting the number of inclusions and
exclusions from the initial search.
areas targeted in the included studies. Most publications used 2
mA intensity for tDCS. Nevertheless, some studies used 1.5 mA
intensity to assess the intervention effects. Stimulation time
ranged between 13 and 30 min. However, almost half of the
studies used 20-min protocol (6/14). Single-session tDCS was
performed in two studies [13, 33] while multi-session tDCS was
used in the rest of publications ranging between three sessions
and 8 months of stimulation.
The effects of tDCS on attention
Six records evaluated the impacts of tDCS on attention. Of these,
three publications showed the negative impacts of tDCS on
attention [11, 12, 33] and three publications showed the positive
effects in this regard [34, 35]. Quantitative synthesis revealed the
positive effects of tDCS on attention in patients with AD (0.425
SMD, 95% CI, −0.254 to 1.104, p = 0.220). However, these effects
were not statistically significant (Fig. 2). Here too, we found that
the general heterogeneity of the studies was high (ϰ2 = 22.810,
T2 = 0.552, d.f. = 5, I2 = 78.80%, p < 0.000).
The effects of tDCS on general cognitive tests
Eleven records assessed the effects of tDCS on general cognitive
tests, i.e., the Mini-Mental State Examination (MMSE), Wechsler
Adult Intelligence Scale (WAIS-III), Montreal Cognition Scale, the
Milan Overall Dementia Assessment (MODA), and the Alzheimer’s
Disease Assessment Scale (ADAS). All eleven citations were able to
show the positive effects of tDCS on general cognitive measures.
Quantitative synthesis showed the positive effects of tDCS on
general cognitive measures in patients with AD (1.640 SMD, 95%
CI, 0.782 to 2.498, p < 0.000) (Fig. 3). Again, we found that the
general heterogeneity of the studies was high (ϰ2 = 96.29, T2 =
1.727, d.f. = 10, I2 = 89.61%, p < 0.000).
The effects of tDCS on memory
Six studies evaluated the impacts of tDCS on memory and all of
them showed it positive effects in this regard. Meta-analysis
Molecular Psychiatry
A. Majdi et al.
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showed that tDCS significantly improved memory in patients with
AD (1.031 SMD, 95% CI, 0.688 to 1.373, p < 0.000) (Fig. 4). Opposed
to the other cognitive measures, we found that the general
heterogeneity of the studies was low (ϰ2 = 7.253, T2 = 0.085, d.f. =
5, I2 = 31.06%, p = 0.203).
Results of subgroup analysis
Subgroup analysis revealed that low current intensity, as opposed
to high current intensity tDCS, has a significant effect on
improvement of attention in AD patients (p = 0.000). Also, tDCS
on both temporal lobe and left DLPFC significantly improved
memory in AD patients (p = 0.000 for both comparisons). Further,
low current density and repeated tDCS had significant impact on
the improvement of memory in these patients (p = 0.000 for both
comparisons). Besides, both high (p = 0.000) and low (p = 0.009)
stimulation times had statistically significant effects on memory
function. The stimulation site (left DLPFC (p = 0.015) and temporal
lobe (p = 0.007)), current density (low (p = 0.030) and high (p =
0.003)), number of sessions (repeated (p = 0.000)), and stimulation
time (low (p = 0.000)) were also found to have significant effects
on general cognitive function in the patient group (Table 2).
Categorizations are from Cai et al. study [36].
Leave-one-out sensitivity analysis
To evaluate the robustness of the association results, we conducted a
leave-one-out sensitivity analysis by iteratively removing one study at
a time and recalculating the summary SMD. This analysis showed that
the results were stable meaning that that they will not significantly
change by the exclusion of any single study.
Publication bias and study quality
The Cochrane Risk of Bias Tool was applied for the detection of
publication bias. All of the publications had been published in peer-
reviewed journals. The results showed no selective (reporting bias)
and incomplete outcome data reporting, (0%). However, one study
did not observe random sequence generation, one record did not
 4
Table 1. Characteristics of the included studies in the systematic review.
Author, Ref. Study design Cognitive domain Mean age Gender MMSE Level of Participants Anode location Cathode location Current Electrode Stimulation Number Outcome(s) Dropout Adverse events
(M/F) education (mA) size (cm2) Time (min) of
(years) sessions
Liu et al. [33] Crossover General Memory 77.9 ± 5.3 6/4 NM 16 ± 3 10 The left and right The inion (Iz) 2 35 20 3 Improvements in 0 0
dorsolateral specific memory
prefrontal cortex tasks can be safely
achieved after a
single-session
Boggio et al. Crossover Memory 79.1 ± 8.8 4/6 12–25 8.7 ± 4.9 10 The left temporal The right 2 35 30 Single tDCS enhanced a 0 0
[13] cortex, left dorsolateral supraorbital area component of
prefrontal cortex recognition memory
Boggio et al. Crossover Attention General 77.5 ± 6.9 8/7 21.0 ± 3.2 13.3 ± 4.8 15 The temporal lobes The right 2 30 30 5 Performance in a 0 0
[12] for Italian for Italian for Italian bilaterally deltoid muscle visual recognition
80.6 ± 9.5 19.0 ± 2.8 15.7 ± 0.8 memory test
for for for significantly
Brazilian Brazilian Brazilian improved
Bystad et al. Parallel Attention 70.0 ± 8.0 7/5 20.0 ± 2.8 NM 12 The left NM 2 35 30 10 tDCS did not 1 0
[18] General Memory temporal cortex significantly improve
verbal memory
function
Cespón Crossover Attention 70.2 ± 5/7 NM NM 12 The left dorsolateral The right shoulder 1.5 16 13 Single Slight tendencies NM NM
et al. [34] 5.12 prefrontal cortex between enhanced
working memory
and increased P200
after cathodal tDCS
were observed.
Ferruci Crossover Attention Memory 75.2 ± 7.3 3/7 22.7 ± 1.8 10.9 ± 4.8 10 The temporal lobes The right 1.5 NM 15 3 tDCS specifically 0 NM
et al. [11] bilaterally deltoid muscle improved a
recognition memory
performance
Im et al. [39] Parallel General Memory 71.9 ± 9.2 1/10 20.1 ± 3.8 6.3 ± 3.8 11 The dorsolateral NM 2 36 30 6 months tDCS may improve or 2 NM
prefrontal cortex stabilize cognition
A. Majdi et al.

Khedr et al. Parallel (RCT) General 65.5 ± 7.8 19/15 18.4 ± NM 23 The left dorsolateral The contralateral 2 24 25 10 Repeated sessions of 0 2
[40] for anodal (sham 3.9 anodal prefrontal cortex supraorbital region tDCS could not
68.3 ± 5.9 included) 18.8 ± 2.9 improve cognitive
for cathodal function
cathodal
Khedr et al. Parallel (RCT) Attention General 64.22 ± 13/10 NM 4.04 ± 2.83 23 The left and right The right 2 35 20 10 tDCS applied over 2 2
[35] 3.64 temporoparietal region deltoid muscle the temporoparietal
region can improve
cognitive function
Suemoto Parallel (RCT) Attention Memory 79.4 ± 7.1 5/15 15.2 ± 2.9 5.0 ± 4.2 20 The left dorsolateral Right supraorbital 2 35 20 6 No significant effects 2 Reported but
et al. [36] prefrontal cortex on cognition were the number is
reported unclear
Gangemi Parallel General 67.5 ± 2.8 10/16 14.9 ± 1.8 6.5 ± 2.0 26 The left Right frontal lobe 2 25 mm 20 10 Anodal tDCS is an 2 NM
et al. [29] frontotemporal cortex effective method to
delay the
Gangemi Parallel General 68 ± NM 6.7 ± 2.0 18 The left Right frontal lobe 2 25 mm 20 80 progression of 2 NM
et al. [29] 0.52.8 frontotemporal cortex Alzheimer’s disease
both in the short and
long terms.
Inagawa Parallel General 76.6 ± 5.7 NC NM NC 5 The dorsolateral The contralateral 2 35 20 10 No statistically 0% in the 11
et al. [19] prefrontal cortex supraorbital ridge significant cognitive active
effects of tDCS in group and
patients with mild or 7.69% in
major the
neurocognitive sham group
disorders was
reported.
Gangemi Parallel General Aged 9/6 NM 6.8 15 The left temporal The contralateral NM 35 NM 10 tDCS increased NM 0
and Fabio 70 to 85 cortex, left dorsolateral supraorbital ridge cognitive functions
[30] prefrontal cortex in terms of temporal
orientation, spatial
orientation, reversal
learning, verbal
intelligence, story,
production of word,
and attention
Case reports
Andrade et al. [50] NM 1 The dorsolateral Right supraorbital 2 35 30 10 tDCS had a stabilizing impact on overall cognitive
prefrontal cortex function and led to enhanced performance on all the
secondary outcome tests.

Molecular Psychiatry
 A. Majdi et al.
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Adverse events

tDCS could be used to improve cognitive symptoms in

blind the participants and personnel, and another did not perform

tDCS could be used as a safety adjunctive therapeutic

Accelerated tDCS may stabilize cognitive functions in

8 months tDCS could slow the cognitive decline in Alzheimer`s

allocation concealment (8.3%) (performance bias). Also two studies
Alzheimer’s disease, particularly verbal memory
did not perform blind outcome assessment (16.66%) (detection bias).
These suggest overall good quality of the included studies (Fig. 5).
Dropout

DISCUSSION
tool in Alzheimer`s disease Summary of evidence
degenerative diseases.

This focused systematic review and meta-analysis investigated the

effects of single-session or multi-session tDCS on the cognitive
function in patients with AD. Together, the meta-analytic
Outcome(s)

techniques conducted on the 23 comparisons from 13 qualified

disease.

studies support the conclusion that the tDCS protocols had

positive effects in ameliorating the AD-induced cognitive dysfunc-
sessions

tion in memory and global cognitive domains. However, changes

Number

in the attention domain did not reach statistical significance. This

12

10
of

is meta-analysis assesses the effects of tDCS on cognitive function

Stimulation

in AD patients. Given the increasing application of tDCS in

Time (min)

modifying cognitive function in healthy populations, and also in

the treatment of memory dysfunction in clinical cohorts, we felt
30

30

30

30

NM not mentioned, NC not clear, tDCS transcranial direct-current stimulation, MMSE Mini-Mental State Examination, RCT randomized clinical trial.

that such a systematic review and meta-analysis was necessary to

size (cm2)
Electrode

better delineate the impacts attained thus far with this

technology.
NM

NM

NM
35

Comparison with other studies

Current

The current findings on the impacts of tDCS for cognitive

(mA)

dysfunctions after AD are inconsistent. To date, two previous

fronto-polar cortex

quantitative reviews and one meta-analysis have explored the

Cathode location

The contralateral

effects of tDCS on cognitive dysfunction in dementia and MCI

frontal lobe

frontal lobe

[19, 21, 36]. In a meta-analysis by Cai et al. on the effects of tDCS

The right

The right

on cognitive function, it was found that tDCS has a beneficial

NM

effect in mild to moderate AD patients. This meta-analysis

included seven studies (as opposed to 14 studies in our meta-
Brodmann areas 39/40
The left temporal lobe

The left temporal lobe

The left dorsolateral

analysis), however, it did not categorize them to different

prefrontal cortex
Anode location

cognitive subgroups, nor compute a combined effect across

multiple outcomes in a single study [36]. These were clear sources
of heterogeneity in our study that were avoided by categorizing
the studies to memory, general and attention groups and also by
calculating the mean for multiple outcomes reported for a single
Participants

subdomain. Inagawa et al. conducted a meta-analysis on

11 studies and showed a lack of strong indication regarding the
efficacy of multi-session anodal tDCS due to the limited number of
1

studies and different measures used [19]. Contrary to our study,

education
Level of

this study was performed on both AD and MCI patients. On the

(years)

other hand, Cruz Gonzalez et al. performed a meta-analysis on

12 studies with 195 patients with dementia (PwD) and four with 53
patients with MCI (PwMCI). This study found that tDCS enhances
MMSE

14.27

memory in PwD in the short term, and has mild positive impact on
NM
19

20

memory and language in PwMCI [21]. However, this meta-analysis

was not performed exclusively on patients with AD either. Also,
Gender
(M/F)

Roncero et al. assessed the effects of inferior parietal tDCS along

with training on cognition in anomic AD and frontotemporal
Mean age

dementia and showed significantly improved cognitive function

(40% vs. 19%, p < 0.01) and a small increase for untrained picture‐
naming items and digit span, lasting at least 2 weeks after
stimulation [37]. Nevertheless, the latter study was performed on a
Cognitive domain

mixed group of patients with AD and frontotemporal dementia

and evaluated tDCS plus training effects in this group.

Insights into individual studies

Boggio et al. investigated the procognitive effects of anodal tDCS
Study design
continued

(atDCS) on recognition and working memory in ten AD patients over

the left temporal cortex and DLPFC [13]. In another study, these
authors showed long-term improvement of visual recognition
Bystad et al. [18]

Bystad et al. [18]

Masse et al. [52]

Costa et al. [51]

memory for up to 4 weeks after tDCS in 15 AD patients [12]. Ferrucci

Author, Ref.
Table 1.

et al. assessed the cognitive impacts of tDCS over the temporoparietal

areas in patients with AD and revealed an enhancement in a word-
recognition memory in ten patients with probable AD. On the other

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 A. Majdi et al.
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Fig. 2 Forest plot of standardized mean difference (SMD) for attention after transcranial direct-current stimulation in patients with
Alzheimer’s disease. Green square shows overall pooled effect. Black squares indicate the SMD in each study. Horizontal lines represent 95%
confidence interval (CI).

Fig. 3 Forest plot of standardized mean difference (SMD) for general cognitive measures after transcranial direct-current stimulation in
patients with Alzheimer’s disease. Green square shows overall pooled effect. Black squares indicate the SMD in each study. Horizontal lines
represent 95% confidence interval (CI).

Fig. 4 Forest plot of standardized mean difference (SMD) for memory after transcranial direct-current stimulation in patients with
Alzheimer’s disease. Green square shows overall pooled effect. Black squares indicate the SMD in each study. Horizontal lines represent 95%
confidence interval (CI).

hand, cathodal tDCS (ctDCS) deteriorated word-recognition memory
in the same patients and the effects last up to 30 min after stimulation
[11]. Cespon et al. evaluated the effects of tDCS on 12 patients with
AD and revealed that ctDCS improved working memory and
increased P200 amplitude and frontal theta activity between 150
and 300 ms in AD patients [33]. Gangemi et al. assessed both the long
and short term effects of tDCS in 18 and 26 patients with AD,
respectively. Results showed that tDCS was effective both in the short-
and the long-term to prevent the progression of AD [29]. In another
study, Im et al. found that 6-month at-home tDCS over the DLPFC in
11 patients with AD improved global cognitive function assessed by
MMSE and language evaluated by Boston Naming Test, but not
delayed recall performance [38]. Other investigations conducted by
Khedr et al. assessed the long-term efficacy of tDCS in the
neurorehabilitation of 34 AD patients. Intriguingly, it was revealed
that both a- and ctDCS improved MMSE in contrast to sham tDCS.
However, this was the case for ctDCS in the performance IQ [34, 39].
On the other hand, Suemoto et al. found that six sessions of
intervention over DLPFC in 40 patients with moderate AD had no
effect on secondary outcomes i.e., global cognition and neuropsy-
chiatric symptoms [35].
Factors influencing response to tDCS
Apparently conflicting results in the assessed studies may stem
from variability in the function of the brain that is being assessed,
e.g., memory, attention, learning, and/or from variabilities in the
tDCS parameters used e.g., current intensity and density in the
region of interest, electrode size and location, stimulation time,
and number of sessions. It may also result from interindividual
differences in cranial and brain anatomy such as skull thickness,
subcutaneous fat, gyral pattern, local tissue heterogeneities, and
orientation of neurons, all of which influence current distribution
especially in patients with AD who suffer from various degrees of
brain atrophy. The functional organization of local inhibitory and
excitatory circuits within the cortex, a participant’s initial level of
function, interindividual differences in the neurophysiological
response to tasks performed during tDCS, different levels of
neurotransmitters and receptor sensitivity, genetics, and age are
also among factors which affect individual response to tDCS (20). If
effects of tDCS are mediated by co-stimulation of peripheral
nerves, then patient specific cranial and cervical nerve anatomies
may also play a role [8]. Accordingly, individualized current
simulation could be suggested as a way to optimize the effects.

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Table 2. The results of subgroup analysis in the three main domains of study.

Attention
Subgroup No. of Studies SMD Lower limit Upper limit P value
Stimulation site Left DLPFC 2 0.383 −0.707 1.475 0.490
TL 4 0.435 −0.571 1.442 0.396
Current density (mA/cm2) High (≥0.08) 2 −0.353 −0.891 0.185 0.198
Low (≤0.08) 4 0.965 0.583 1.348 0.000
No. of sessions Single 1 – – – –
Repeated 5 0.548 −0.210 1.307 0.156
Stimulation time (min) Low ≤20 4 0.502 −0.316 1.320 0.229
High >20 2 0.289 −1.246 1.824 0.712
Memory
Subgroup No. of Studies SMD Lower limit Upper limit P value
Stimulation site Left DLPFC 3 1.095 0.211 1.980 0.015
TL 2 1.237 0.596 1.877 0.000
Current density (mA/cm2) High (≥0.08) 1 – – – –
Low (≤0.08) 5 1.039 0.675 1.404 0.000
No. of sessions Single 1 – – – –
Repeated 5 1.030 0.647 1.413 0.000
Stimulation time (min) Low ≤20 3 1.303 0.321 2.285 0.009
High >20 3 1.005 0.515 1.495 0.000
General
Subgroup No. of Studies SMD Lower limit Upper limit P value
Stimulation site Left DLPFC 5 1.732 0.342 3.123 0.015
TL 5 0.869 0.235 1.504 0.007
Current density (mA/cm2) High (≥0.08) 6 1.494 0.511 2.477 0.003
Low (≤0.08) 4 0.894 0.086 1.703 0.030
No. of sessions Single 0 – – – –
Repeated 11 1.639 0.782 2.497 0.000
Stimulation time (min) Low ≤20 5 1.202 0.869 1.535 0.000
High >20 5 1.416 0.003 2.829 0.050
Lines in bold are statistically significant.
SMD standardized mean difference, TL temporal lobe, DLPFC dorsolateral prefrontal cortex.

It is worth pointing out that the effect of tDCS has been
repeatedly linked to the number of sessions. Most of the articles
included in the meta-analysis submitted their patients to less than
10 sessions. In that light, Brunoni et al. [40], reported that patients
who received 12 tDCS sessions were more than 5 times likely to
respond than those receiving an even slightly lower total dose
(e.g., missing two such sessions), and the difference in benefit
became even greater compared with doses that were lower still.
Randomization and blinding
Randomization and blinding are decisive tools in defining the
efficacy of a novel intervention. Nevertheless, randomization is not
able to overcome poor technique or experimental design [41]. It
has been found that human clinical trials that are devoid of
randomization or blinding frequently overestimate the effect size
[20]. In this meta-analysis, all of the included studies, except one
[33], were randomized and double-blinded. Three studies were at
the same time randomized clinical trials. This increased the
robustness of our meta-analysis.
A mechanistic view on the procognitive effects of tDCS in AD
The pathways by which tDCS modulates brain activity could be
divided into two broad categories, i.e., transcranial and transcuta-
neous routes [4]. In the transcranial route, tDCS recovers cognitive
performance via the modulation of the target areas that promote
the relevant cognitive functioning [42]. It has been generally
postulated that tDCS has synaptic and non-synaptic after effects
and changes cerebral blood flow (CBF) [43], neuronal as well as
oscillatory brain activity by altering the membrane potential [44],
neurotransmitters levels polarity-dependently (NMDA receptor-
dependent after effects [45], GABAergic interneurons, and
glutamatergic synapses [46]), and functional connectivity patterns
in the brain. As AD patients have altered neuronal activity and the
CBF due to changes in microvasculature and synapses, altered
brain oscillations, and changes in network connectivity, tDCS may
interact differently than in a healthy brain [47]. Increasing cortical
excitability could be another mechanism by which tDCS improves
memory in AD patients, as AD patients reveal temporoparietal
hypoactivity [48]. As with previous studies [42], our meta-analysis
included records that mainly targeted the DLPFC and the
temporoparietal cortex which are the crucial nodes of the common
memory network and are affected by tDCS and AD.
In the transcutaneous route, tDCS recovers brain function via
pathways which are mainly activated through peripheral nerves
such as trigeminal and greater occipital nerves. These intercon-
nected nerves reach their targets in the brainstem via their
projections to the nucleus of the solitary tract (NTS) and trigeminal
nuclei. Accordingly, the information travels to the reticulation

Molecular Psychiatry
 A. Majdi et al.
8
Fig. 5 Percentage of different levels of risk of bias for each item in
included studies. The Cochrane risk of bias tool was used for
detection of publication bias.
formation of the brain and ascending reticular activating system
(ARAS). The key role of locus coeruleus (LC), as part of the ARAS,
should not be neglected here. Upon activation, LC releases
norepinephrine (NE) which reaches its target areas in the brain
such as cortex, hippocampus, amygdala, and etc. and modulates
their activity. As has been recently shown tDCS co-stimulation of
cranial and cervial nerves can modulate attention, perceptual
rivalry and memory formation and retrieval [4, 8]. Thus, the results
reported in this meta-analysis may be due to tDCS co-stimulation
of peripheral nerves in the scalp. Improved experiments using
conditions which control for co-stimulation of peripheral nerves
and needed to separate the transcranial and transcutaneous
effects of tDCS on AD.
What is needed for tDCS to become the new treatment for
AD?
Defining the moment research could be considered adequately
mature to come from bench to bedside and support the
establishment of a therapy is ethically intricate. Evidence-based
guidelines on the therapeutic use of tDCS indicate that all studies
performed in the field provide Class II level of evidence to conduct
tDCS in patients with AD. However, the guidelines give no
recommendation for anodal tDCS of the left DLPFC to improve
cognitive performance in AD [49]. This does not mean that this
approach should be considered as only investigational, because
sufficient evidence regarding the safety and efficacy of tDCS in AD
and other non-AD dementias has been established to validate the
intervention as a treatment. On the other hand, evidence from this
meta-analysis indicates that additional, well-designed, double-
blinded clinical trials are needed before tDCS can be considered as
an effective treatment for AD.
Limitations
There are several limitations in the present meta-analysis. First,
substantial methodological differences existed among the
included records. These included variations in electrode mon-
tages, stimulation polarity, session duration, current intensity and
density, the use of “offline” vs. “online” protocol and stimulation
protocols [15] resulting in the high heterogeneity among the
included citations. Second, when more than one index was
reported for a single outcome measure within a study, we
combined the data according to the methods mentioned in the
statistics. Accordingly, the results of this study may be influenced
by this statistical process. Third, this study included publications
from patients with all stages of AD. Thus, its results may be
affected by this heterogeneity among studies. Fourth, the results
of this study were based on the existing data extracted from
included articles. Accordingly, it is just hypothesis generating
meaning that its data should not be treated as facts. Fifth, the
results of this study might be complicated by bias, as the
heterogeneity among the included studies was high. Sixth,
unreported or negative results are important sources of bias in
biological studies. The included papers in this study may suffer
from this issue too. Such unreported outcomes may have had a
significant effect on the meta-analysis.
CONCLUSION
This meta-analysis found modest evidence supporting that tDCS on
the DLPFC or temporal lobes improve cognitive function namely
memory and general cognitive domains in AD patients. The effects for
attention domain did not reach statistical significance. However, the
heterogeneity of the included studies was shown to be high
indicating weak robustness evidence of the effectiveness of tDCS. In
that light, due to the heterogeneity of stimulation methodologies and
consequent effect sizes, results should be carefully interpreted,
meaning that they do not indicate the use of tDCS for the treatment
of cognitive dysfunction in AD patients. Instead, they point out the
fact that larger well-designed studies, with adequate controls for
peripheral nerve co-stimulation, still need to be performed.
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ADDITIONAL INFORMATION
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in a case of dementia. NeuroRehabilitation. 2017;41:567–75. https://doi.org/ Reprints and permission information is available at http://www.nature.com/
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