REVIEW
CURRENTOPINION Therapeutic noninvasive brain stimulation in
Alzheimer’s disease and related dementias
Copyright ©
www.co-neurology.com
a,� a,� a,b
Stephanie S. Buss , Peter J. Fried , and Alvaro Pascual-LeonePurpose of review
Alzheimer’s disease is a progressive neurodegenerative disease without effective pharmacologicaltreatment. Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magneticstimulation (TMS) and transcranial electrical stimulation (tES), are increasingly being investigated for theirpotential to ameliorate the symptoms of Alzheimer’s disease and related dementias (ADRD).
Recent findings
A comprehensive literature review for primary research reports that investigated the ability of TMS/tES toimprove cognition in ADRD patients yielded a total of 20 reports since 2016. Eight studies used repetitiveTMS and 12 used transcranial direct current stimulation, the most common form of tES. Eight of the studiescombined NIBS with cognitive training. Promising results should encourage continued investigation,however there is currently insufficient evidence to support widespread adoption of NIBS-based clinicaltreatments for ADRD.
Summary
NIBS remains an active area of investigation for treatment of ADRD, though the predominance of small,heterogeneous, proof-of-principle studies precludes definitive conclusions. We propose the establishment ofa consortium to achieve the benefits of large-scale, controlled studies using biomarker-based diagnosticcharacterization of participants, development of neurophysiological markers to verify target engagement,and standardization of parameters.
Keywords
Alzheimer’s disease, mild cognitive impairment, noninvasive brain stimulation, repetitive transcranialmagnetic stimulation, transcranial electrical stimulation
aDepartment of Neurology, Berenson-Allen Center for Noninvasive BrainStimulation and Division of Cognitive Neurology, Beth Israel DeaconessMedical Center, Harvard Medical School, Boston, Massachusetts, USAand bInstitut Guttmann de Neurorehabilitacio, Universitat Autonoma deBarcelona, Badalona, Spain
Correspondence to Alvaro Pascual-Leone, Berenson-Allen Center forNoninvasive Brain Stimulation, Beth Israel Deaconess Medical Center,330 Brookline Ave (KS 158), Boston, MA 02215, USA.Tel: +1 617 667 0307; fax: +1 617 975 5322;E-mail: [email protected]�Stephanie S. Buss and Peter J. Fried contributed equally to this article.
Curr Opin Neurol 2019, 32:292–304
DOI:10.1097/WCO.0000000000000669
INTRODUCTION
Alzheimer’s disease is the most common cause ofdementia worldwide [1]. With the growth of theaging population, the prevalence of Alzheimer’sdisease in the United States alone is projected torise from 5.5 to 13.8 million by 2050 unless newtreatments to prevent, slow, or reverse the diseaseare developed [2]. Currently available medicationsfor Alzheimer’s disease may offer some symptomaticrelief [3,4], but do not alter the underlying diseaseprocess or pathology. Recent drug trial failures forAlzheimer’s disease and related dementias (ADRD)have left the field with a lack of disease-modifyingtherapies [5,6]. In this context, nonpharmacologicalinterventions including lifestyle modifications,physical activity, cognitive training, and noninva-sive brain stimulation (NIBS) have been increasinglyinvestigated as potential treatments or symptomatictherapies for Alzheimer’s disease -related cognitivedecline [7–10]. This review will focus on the twomost widely studied NIBS techniques to-date,
2019 Wolters Kluwer H
transcranial magnetic stimulation (TMS) and trans-cranial electrical stimulation (tES). However, wewant to emphasize that given the complex patho-physiologic nature of ADRD, a single therapeuticintervention is unlikely to be a satisfactory response,and that combination of various interventionsis probably critical. NIBS has the appeal thatcan be easily combined with pharmacologic and
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Volume 32 � Number 2 � April 2019
KEY POINTS
� NIBS with or without cognitive training has thepotential to improve cognition in ADRD.
� A paucity of large-scale trials and a lack of consistencyin treatment parameters precludesdefinitive conclusions.
� The use of available biomarkers would greatly improvediagnostic characterization of ADRD patients.
� Neurophysiological or modeling-based indicators areneeded to confirm the engagement of cortical targetsand monitor stimulation efficacy.
� The field would benefit from a consortium or othermultisite coordinated efforts.
Noninvasive brain stimulation in Alzheimer’s disease Buss et al.
behavioral interventions, and may play a useful rolein future multimodality treatment approaches thatare likely to be needed in ADRD.
TMS is a means of inducing brief pulses of intra-cranial electrical currents with a powerful, rapidlyfluctuating, handheld electromagnet [11]. A singlepulse of TMS can depolarize neuronal membranesleading to action potentials. TMS of the primarymotor cortex can evoke descending corticospinalvolleys, which can give rise to activations of contra-lateral muscles. These can be recorded as motorevoked potentials via electromyography. TMS tomotor or nonmotor regions can also elicit intracra-nial TMS-evoked potentials that can be recorded viaelectroencephalography and are presumed to be theresults of activation of cortical neural elements.Delivering trains of TMS pulses at a specified fre-quency and intensity, termed repetitive TMS(rTMS), can induce changes in brain excitability thatcan persist for some time after the period of stimu-lation [12]. The immediate aftereffects of a singlerTMS application are typically measured as changesin the performance of a behavioral task or somemeasure of cortical excitability, such as the averageamplitude of motor evoked potentials or TMS-evoked potentials. Daily sessions of rTMS arethought to yield a cumulative effect and form thebasis for the stimulation protocols used with devicescleared by the US Food and Drug Administrationfor clinical treatment of patients with medication-resistant major depression [13] and obsessive-compulsive disorder [14].
In ADRD, several small pilot studies have shownpromise using rTMS protocols to improve globalcognition or language function [15–17], eitherusing rTMS alone or combined with cognitivetraining. One example is the NeuroAD protocol(Neuronix Ltd., Yoqneam, Israel), in which rTMS
Copyright © 2019 Wolters Kluwe
1350-7540 Copyright � 2019 Wolters Kluwer Health, Inc. All rights rese
is delivered to six brain regions and paired withinterleaved cognitive training of the function asso-ciated with the targeted brain region [18]. Therehave been several early proof-of-principle studiesusing the NeuroAD protocol [15,16]. In 2016, alarge multisite clinical trial (ClinicalTrials.gov:NCT01825330) was completed and awaits a finaldeclaration by the US Food and Drug Administration.
The other major form of NIBS is tES, whichinvolves passing weak electrical current betweentwo or more electrodes placed on the scalp[19,20]. The most common form of tES is trans-cranial direct current stimulation (tDCS), in whicha constant current (typically 1–2 mA) is applied tocreate electrical gradients, which are thought tomodulate cortical excitability indirectly by increas-ing (depolarizing) or decreasing (hyperpolarizing)the resting membrane potentials of neural elementsin the vicinity of the anode or the cathode, respec-tively [21,22].
In ADRD, tDCS has been studied as a therapeutictool in several pilot studies, and has shown promisein improving memory performance [23–25]. Otherforms of tES include transcranial alternating currentstimulation (tACS), in which the current is rapidlyalternated at a specific frequency to entrain corticaloscillations, and transcranial random noise stimu-lation (tRNS), in which a full-band current spectrumis applied to boost endogenous rhythms by means ofstochastic resonance [26]. Although there have notbeen many studies using tACS in ADRD to date, it isan appealing approach given evidence of abnormalbrain oscillations in Alzheimer’s disease [27]. Simi-larly, although there have not been any publishedreports investigating the potential therapeutic ben-efit of tRNS in ADRD, it has been shown to improvefluid intelligence in healthy adults when paired withadaptive cognitive training [28]. Future studies mayexplore the potential of these and other new NIBStechniques for ADRD.
The purpose of the present review is to assessrecent developments in the investigation of NIBS astreatment for ADRD. Although preliminary studiesof TMS and tDCS have shown evidence of improvingspecific cognitive domains Alzheimer’s disease,there is at present no clear consensus about whichNIBS paradigms are the most promising for treat-ment of ADRD, and which, if any, might be disease-modifying vs. simply symptomatic. Given the rap-idly changing state of the field, this review includesonly recent studies from 2016 to 2018 and focuseson those investigations into the clinical benefit ofNIBS to treat Alzheimer’s disease. For state of thefield before 2016, we refer to a prior review byGonsalvez et al. [7]. Since 2016, there have been anumber of studies investigating the diagnostic
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rved. www.co-neurology.com 293
Degenerative and cognitive diseases
[29,30] or prognostic [31] potential of NIBS forADRD, or to better understand its pathophysiology[32,33], but these are outside the scope of thisreview. We will discuss commonalities and discrep-ancies across interventional studies and point outareas where further investigation is needed. Finally,we will discuss future directions, including oppor-tunities offered by novel technologies in NIBS.
METHODS
A literature search was performed in PubMed usingthe following Boolean combinations of termsrelated to ADRD (’Alzheimer’s,’ ‘mild cognitiveimpairment (MCI),’ ‘dementia’) and those relatedto NIBS (’noninvasive brain stimulation,’ ‘noninva-sive brain stimulation,’ ‘TMS,’ ‘rTMS,’ ‘theta burststimulation,’ ‘transcranial electrical stimulation,’‘transcranial current stimulation,’ ‘tDCS,’ ‘ tACS,’and ‘tRNS’). Articles with a publication date prior to1 January 2016 were excluded as they were reviewedand discussed in Gonsalvez et al. [7]. Abstracts werereviewed and selected for inclusion if they repre-sented a case study, case series, pilot or proof-of-principle study, or randomized control study for theuse of NIBS as a treatment for Alzheimer’s disease orMCI, with a primary aim of improving cognitivefunction. Studies focusing primarily on other dis-ease pathologies or other diagnostic groupings werenot included.
Copyright © 2019 Wolters Kluwer H
FIGURE 1. Investigations of NIBS for treatment of ADRD sincedisease; FTD, frontotemporal dementia; LBD, Lewy body disease;stimulation; PD, Parkinson’s disease; PDD, Parkinson’s disease decognitive impairment; VaD, vascular dementia.
294 www.co-neurology.com
RESULTS
Figure 1 shows a flow diagram of the PubMed search.The literature search yielded 39 studies focused ontreatment of neurodegenerative disorders usingNIBS techniques from 2016 to 2018; 20 of thesefocused on the treatment of cognition in Alz-heimer’s disease or MCI were included in thisreview. The additional 19 studies investigated NIBStreatments for other neurodegenerative patholo-gies, and included primary progressive aphasia,frontotemporal dementia, MCI because of Parkin-son’s disease, Lewy body disease, and other condi-tions outside of the scope of the current review.
Trials using repetitive transcranial magneticstimulation in Alzheimer’s disease andrelated dementias
Table 1 lists the eight articles focusing on rTMStreatment of Alzheimer’s disease that were includedin the review. Six of the eight studies focused onpatients meeting criteria for Alzheimer’s diseasedementia [34
&
,35&&
,36,37&
,38&
,39&
], whereas twostudies focused on early-stage Alzheimer’s disease(prodromal Alzheimer’s disease or MCI) [40
&&
,41&
].Determination of MCI or Alzheimer’s disease statuswas primarily based on clinical diagnostic criteriawith one study used cerebral spinal fluid (CSF) bio-markers to confirm the diagnosis [40
&&
].Parameters of rTMS stimulation (including
intensity, frequency, duration, and number of
ealth, Inc. All rights reserved.
2016. Flow diagram of literature search. AD, Alzheimer’sMCI, mild cognitive impairment; NIBS, noninvasive brainmentia; PPA, primary progressive aphasia; SCI, subjective
Volume 32 � Number 2 � April 2019
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Tab
le1
.St
udie
sin
vest
igat
ing
tran
scra
nial
mag
netic
stim
ulat
ion
asa
ther
apeu
ticto
olin
AD
RD
TMS
stu
die
s
20
16
–2
01
8
(ref
eren
ces)
Cri
teri
afo
r
AD
/MC
I
(dis
ease
sta
ge)
No
.o
f
pa
rtic
ipa
nts
Sha
m/
cont
rol
Ag
e
(mea
n
�SD
)
Targ
eta
rea
;
loca
liza
tio
n
met
ho
d
Inte
rlea
ved
cog
niti
ve
tra
inin
g
Inte
nsi
ty
(%R
MT)
TMS
freq
uen
cy
an
dp
att
ern
Stim
ula
tio
nd
ura
-
tio
n;
nu
mb
ero
f
TMS
tra
ins;
nu
mb
er
of
pu
lses
/da
y
Len
gth
of
inte
rven
tio
n;
ium
ber
of
sess
ion
s
Co
gn
itiv
e
do
ma
in
Neu
rop
sych
o-
log
ica
lte
sts
–
pri
ma
ry
ou
tco
me
Neu
rop
sych
o-
log
ica
lte
sts
–
seco
nd
ary
ou
tco
mes
Ma
insg
nif
ica
nt
neu
rop
sych
olo
gic
al
fin
din
gs
Pilo
tst
udie
san
dRC
Ts
[35&
&
]Pr
obab
leA
Dba
sed
onD
SM-IV
crite
ria,
CD
R1
–2,
MM
SE
18
–26
(mild
–
mod
erat
eA
D)
26
2:1
treat
men
t:
sham
Trea
tmen
tgro
up
age¼
71.2�
7.6
,
sham
gro
up
age¼
70.3�
4.8
Six
brai
n
regio
ns;
MRI
gui
ded
Yes
90
–110%
RMT
10
Hz
rTM
S;20
train
s
appl
ied
with
2s
on,
20
–40
sof
f;w
ith
inte
rleav
edco
gni
tive
task
1h
sess
ion/
day;
thre
ebr
ain
regio
ns/d
ay;
1200
pulses
/day
6w
eeks
;30
sess
ions
Glo
bal
cogni
tion
AD
AS-
Cog
MM
SE;
CG
IC;
GD
S
Ther
ew
asa
signi
fican
t
impr
ovem
enta
fter
the
inte
rven
tion
inA
DA
S-
Cog
inth
etre
atm
ent
gro
up,
butt
hebe
twee
n-
gro
updi
ffere
nce
com
pare
dw
ithsh
am
was
nots
igni
fican
t.In
both
treat
men
tand
sham
,th
ela
rges
t
impr
ovem
entw
asse
enin
mild
AD
com
pare
dto
mod
erat
eA
D
[36]
Prob
able
AD
base
don
DSM
-IVcr
iteria,
CD
R1
–2,
MM
SE
18
–26
(mild
–
mod
erat
eA
D)
30
17:1
3
treat
men
t:
sham
Trea
tmen
tgro
up
age¼
69.3�
5.8
,
sham
gro
up
age¼
71.4�
5.2
Trea
tmen
tare
asno
t
clea
rlysp
ecifi
ed,
buti
nclu
ded
pariet
alP3
/P4,
post
erio
rte
mpo
ral
T5/T
6;
10
–20
syst
em
Yes
Not sp
ecifi
ed
20
Hz
rTM
S;20
train
s
appl
ied
with
10
son
,
20
sof
f;w
ith
inte
rleav
edco
gni
tive
task
s
1h
sess
ion/
day;
3
brai
nre
gio
ns/
day;
nots
peci
fied
6w
eeks
;30
sess
ions
Glo
bal
cogni
tion
and
verb
al
mem
ory
Not
spec
ified
AD
AS-
Cog
,
MM
SE,
MO
CA
,A
VLT
Ther
ew
asa
signi
fican
t
impr
ovem
enti
nA
DA
S-
Cog
,M
MSE
,an
dA
VLT
inth
etre
atm
entg
roup
,
butt
here
was
no
betw
een-
gro
up
diffe
renc
eco
mpa
red
with
sham
.M
ildA
D
show
eda
larg
er
impr
ovem
entc
ompa
red
with
mod
erat
eA
D
[34&
]Pr
obab
leA
Dby
clin
ical
diag
nosi
s,
seve
rity
rang
ing
from
MC
Ito
mod
erat
e-to
-sev
ere
AD
10
Non
eA
ge¼
70.3
(7.2
)Si
xbr
ain
area
san
d
LD
LPFC
and
R
DLP
FC;
MRI
gui
ded
Yes
100%
RMT
Six
brai
nre
gio
n
treat
men
t:10
Hz
rTM
S;20
train
s
appl
ied
with
2s
on
over
10
min
;w
ith
inte
rleav
edco
gni
tive
train
ing.
DLP
FC
treat
men
t:10
Hz
rTM
S;5
train
sap
plie
d
with
2s
onov
er2.5
min
;w
ithin
terle
aved
cogni
tive
train
ing
1h
sess
ion/
day;
four
brai
n
regio
ns/d
ay;
up
to1300
pulses
/
day
5w
eeks
;25
sess
ions
Glo
bal
cogni
tion
AD
AS-
Cog
Pref
orm
ance
on
inte
rleav
ed
cogni
tive
train
ing
task
s,M
MSE
,
DuB
ios
scor
e,
FAB,
Stro
opte
st,
loco
mot
orsc
ore,
apat
hysc
ore,
care
giv
erbu
rden
inte
rvie
w,
depe
nden
ce
scor
e
Imm
edia
tely
afte
rth
e
treat
men
tpro
cedu
re,
ther
ew
asim
prov
emen
t
inth
eA
DA
S-C
og,
loco
mot
orsc
ore,
apat
hy
scor
e,an
dde
pend
ence
scor
e.Si
xm
onth
sla
ter,
AD
AS-
Cog
scor
esha
d
retu
rned
toba
selin
e,bu
t
apat
hyan
dde
pend
ence
scor
esco
ntin
ued
tosh
ow
impr
ovem
ent
[40&
&
]Pr
odro
mal
AD
by
Dub
ois,
2016
crite
ria
with
posi
tive
CSF
biom
arke
r
14
Cro
ssov
erde
sign,
with
parti
cipa
nts
rece
ivin
gbo
th
treat
men
tan
d
sham
stim
ulat
ion
Age¼
70.0�
5.1
Prec
uneu
s;M
RI
gui
ded,
stim
ulat
ion
site
conf
irm
edw
ith
sour
ce
loca
lizat
ion
No
100%
RMT
20
Hz
rTM
S;40
train
s
appl
ied
with
2s
on,
28
sof
f
20
min
ofrT
MS;
1600
pulses
/day
2w
eeks
;10
sess
ions
Ver
bal
mem
ory,
EEG
,an
d
TMS-
EEG
Not
spec
ified
RAV
LT,
MM
SE,
FAB,
DSS
T
RAV
LTde
laye
dre
call
show
eda
signi
fican
t
impr
ovem
enta
fter
treat
men
tcom
pare
dw
ith
sham
;ot
her
test
ssh
owed
nom
ain
effe
ctof
treat
men
t
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Tab
le1
(Con
tinue
d)
TMS
stu
die
s
20
16
–2
01
8
(ref
eren
ces)
Cri
teri
afo
r
AD
/MC
I
(dis
ease
sta
ge)
No
.o
f
pa
rtic
ipa
nts
Sha
m/
cont
rol
Ag
e
(mea
n
�SD
)
Targ
eta
rea
;
loca
liza
tio
n
met
ho
d
Inte
rlea
ved
cog
niti
ve
tra
inin
g
Inte
nsi
ty
(%R
MT)
TMS
freq
uen
cy
an
dp
att
ern
Stim
ula
tio
nd
ura
-
tio
n;
nu
mb
ero
f
TMS
tra
ins;
nu
mb
er
of
pu
lses
/da
y
Len
gth
of
inte
rven
tio
n;
ium
ber
of
sess
ion
s
Co
gn
itiv
e
do
ma
in
Neu
rop
sych
o-
log
ica
lte
sts
–
pri
ma
ry
ou
tco
me
Neu
rop
sych
o-
log
ica
lte
sts
–
seco
nd
ary
ou
tco
mes
Ma
insg
nif
ica
nt
neu
rop
sych
olo
gic
al
fin
din
gs
[37&
]D
iagno
sis
ofA
Dby
DSM
-V,
MM
SE�
15,
GD
S-Re
isbe
rg
leve
l2–4
19
1:1
rand
omiz
atio
n
into
two
activ
e
treat
men
tgro
ups:
‘sim
ple’
vs.
‘com
plex
’
stim
ulat
ion
prot
ocol
Sim
ple
gro
up
age¼
73.3�
6.0
;co
mpl
exgro
up
age¼
71�
4.3
Sim
ple
prot
ocol
:
sing
le-site
DLP
FC
stim
ulat
ion.
Com
plex
prot
ocol
:si
x
brai
nre
gio
ns;
10
–20
syst
em
No
100%
RMT
5H
zrT
MS;
30
train
sap
plie
dw
ith
10
sof
f,60
sof
f
Inth
eSi
mpl
ePr
otoc
ol,
sing
le-si
te
stim
ulat
ion
was
appl
ied
toD
LPFC
daily
,in
the
Com
plex
Prot
ocol
,
3br
ain
regi
ons
wer
etre
ated
daily
;
1500
pulse
s/da
y
3w
eeks
;15
sess
ions
Glo
bal
cogni
tion
AD
AS-
Cog
MM
SE,
NPI
,
GD
S,ID
DD
,
CG
I
Both
treat
men
tgro
ups
show
edan
impr
ovem
ent
inA
DA
S-C
og,
MM
SE,
IDD
D,
NPI
imm
edia
tely
afte
rtre
atm
ent,
whi
ch
pers
iste
don
em
onth
late
r.Th
ere
was
no
signi
fican
tdiff
eren
ce
betw
een
the
two
treat
men
tgro
ups
[41&
]M
CId
iagno
sis
by
Pete
rson
’scr
iteria,
MM
SE�
23,
with
apat
hy(A
ES-C
�30).
8D
oubl
e-bl
ind,
rand
omiz
ed,
cros
sove
rde
sign,
with
parti
cipa
nts
rece
ivin
gbo
th
treat
men
tan
d
sham
Gro
up1
age¼
68.0�
10.0
;G
roup
2
age¼
64.0
�9.0
LD
LPFC
;5.5
cm
ante
rior
tom
otor
hots
potl
ocat
ion
No
120%
RMT
10
Hz
rTM
S;75
train
s
appl
ied
with
3s
on,
26
sof
f
37.5
min
ofrT
MS;
3000
pulses
/day
2w
eeks
;10
sess
ions
Apa
thy
AES
-C3M
S,M
MSE
,
TMT
B,TM
TA
,
EXIT
-25,
CG
I,
I-AD
LS,
AD
LS,
ZBS
Ther
ew
asa
signi
fican
t
impr
ovem
enti
nA
ES-C
afte
rth
eac
tive
treat
men
t
com
pare
dto
the
sham
cond
ition
.Th
ere
was
also
signi
fican
t
impr
ovem
enti
n3M
S,
MM
SE,
TMT
A,
and
CG
I-Iin
the
treat
men
t
gro
upco
mpa
red
with
sham
Cas
ere
ports
and
clin
ical
case
series
[38&
]M
oder
ate–
seve
reA
Dby
clin
ical
diag
nosi
s
11
Non
eA
ge¼
76�
7Bi
late
ralp
refron
tal
corte
xus
ing
deep
TMS;
6cm
ante
rior
tom
otor
hots
potl
ocat
ion
No
120%
RMT
10
Hz
deep
TMS,
42
train
s
appl
ied
with
2s
on,
20
sof
f
One
20-m
inse
ssio
n/
day,
2–3
times
per
wee
k,w
itha
min
imum
inte
rval
of1
day
betw
een
sess
ions
20
sess
ions
Glo
bal
cogni
tion
n/a
Min
dstre
ams
and
AC
E
60%
ofpa
tient
sim
prov
ed
onM
inds
tream
s,an
d
77%
show
ed
impr
ovem
ento
nth
eA
CE
com
pare
dto
base
line.
Trea
tmen
twith
dTM
S
signi
fican
tlyim
prov
ed
AC
Esc
ores
ina
subs
et
ofth
em
ostpr
ogre
ssed
patie
nts
[39&
]M
ild-to
-mod
erat
eA
D
clin
ical
diag
nosi
s
30
Non
e;pa
tient
s
treat
edin
two
priv
ate
clin
ics
offe
ring
com
mer
cial
Neu
roA
D
treat
men
ts
Not
repo
rted
Six
brai
nre
gio
ns;
MRI
gui
ded
Yes
90
–110%
RMT
3/4
para
digm
s:10
Hz
rTM
S;20
train
sap
plie
d
with
2s
onov
er10
min
;w
ithin
terle
aved
cogn
itive
train
ing.
1/4
Para
digm
:10
Hz
rTM
S;5
train
sap
plie
dw
ith2
s
onov
er2.5
min
;w
ith
inte
rleav
edco
gniti
ve
train
ing
1h
sess
ion/
day;
thre
ebr
ain
regio
ns/d
ay;
1300
pulses
/day
6w
eeks
;30
sess
ions
Glo
bal
cogni
tion
n/a
AD
AS-
Cog
and
MM
SE
AD
AS-
Cog
and
MM
SEbo
th
impr
oved
post
treat
men
t
com
pare
dto
base
line
scor
es
Stud
ies
inve
stig
atin
gTM
Sfo
rtre
atm
entof
AD
RDus
ing
clin
ical
orbi
omar
ker
diag
nost
iccr
iteria.
Age
issh
own
asm
ean�
SDor
mea
n(S
EM).
Seve
rals
tudi
esfo
llow
edth
eN
euro
AD
prot
ocol
,ta
rget
ing
six
brai
nre
gio
ns:
Rpr
efro
ntal
,L
pref
ront
al,
Rpa
riet
al,
Lpa
riet
al,
Broc
a’s
area
,an
dW
erni
cke’
sar
ea.
AD
,A
lzhe
imer
’sdi
seas
e;3M
S,M
odifi
edM
ini-M
enta
lSta
tus
Exam
inat
ion;
AC
E,A
dden
broo
keC
ogni
tive
Exam
inat
ion;
AD
AS-
Cog
,A
lzhe
imer
’sD
isea
seA
sses
smen
tSc
ale-
cogni
tive;
AD
Ls,
activ
ities
ofda
ilyliv
ing;
AD
RD,
Alz
heim
er’s
dise
ase
and
rela
ted
dem
entia
s;A
ES,
Apa
thy
Eval
uatio
nSc
ale;
AV
LT,
Aud
itory
-Ver
balL
earn
ing
Test
;BD
S,Bl
esse
dD
emen
tiaSc
ale;
CG
I,C
linic
alG
loba
lIm
pres
sion
;C
GIC
,C
linic
alG
loba
lIm
pres
sion
ofC
hang
e;D
LPFC
,do
rsol
ater
alpr
efro
ntal
corte
x;D
SST,
Dig
itSy
mbo
lSub
stitu
tion
Test
;dT
MS,
deep
TMS;
EXIT
-25,
Exec
utiv
eIn
terv
iew
;D
SMIV
,D
iagno
stic
and
Stat
istic
alM
anua
lofM
enta
lDis
orde
rs,
4th
Editi
on;
FAB,
fron
tala
sses
smen
tba
ttery
;G
DS,
Ger
iatri
cD
epre
ssio
nSc
ale;
I-AD
LS,
inst
rum
enta
lac
tiviti
esof
daily
livin
g;
IDD
D,
Inte
rvie
wfo
rD
eter
iora
tion
inD
aily
Livi
ngA
ctiv
ities
inD
emen
tia;
LD
LPFC
,le
ftdo
rsol
ater
alpr
efro
ntal
corte
x;M
MSE
,M
ini-M
enta
lSta
teEx
amin
atio
n;M
OC
A,
Mon
treal
Cog
nitiv
eA
sses
smen
t;N
PI,
Neu
rops
ychi
atric
Inve
ntor
y;RA
VLT
,re
yau
dito
ryve
rbal
lear
ning
test
;RM
T,re
stin
gm
otor
thre
shol
d;TM
S,tra
nscr
ania
lmag
netic
stim
ulat
ion;
TMT,
Trai
lMak
ing
Test
;TM
TA
,tra
ilm
akin
gte
st,
part-
A;
TMT
B,tra
ilm
akin
gte
st,
part-
B;ZBS
,Zar
itBu
rden
Scal
e.
Noninvasive brain stimulation in Alzheimer’s disease Buss et al.
sessions) varied considerable across protocols. Halfof the studies used MRI-guided neuronavigation[34
&
,35&&
,39&
,40&&
]. Brain regions targeted includedthe precuneus, prefrontal cortex, and a multisite6-ROI protocol adapted from NeuroAD. Interleavedcognitive training was included in four of therTMS studies following the NeuroAD approach[34
&
,35&&
,36,39&
]. Two studies employed a sham con-trol [35
&&
,36], two studies employed a crossoverdesign with participants receiving both sham andtreatment conditions sequentially [40
&&
,41&
], andone study compared two different stimulation para-digms [37
&
].The primary cognitive outcome measures stud-
ied included global cognition, verbal memory, andapathy. Overall, results suggested a potential forimprovement in cognitive measures after rTMStreatments, but results were mixed as to whetherrTMS was significantly more effective than sham.
Trials using transcranial electrical stimulationin Alzheimer’s disease and related dementias
Table 2 lists the 12 trials using tES as a treatmentin Alzheimer’s disease that were included in thereview. Alzheimer’s disease and MCI diagnoses weremostly made clinically [42
&&
,43&
,44&&
,45&
,46,47&&
,48,49,50
&
,51&
,52&
], aside from one case report ofposterior cortical atrophy [53
&
] which confirmedAlzheimer’s disease biomarker positivity usingCSF. Five studies focused on MCI [43
&
,44&&
,45
&
,46,47&&
]. One case series examined the use oftES for treatment of auditory hallucinations in Alz-heimer’s disease and Lewy body disease [51
&
], andanother case report examined tES for treatment oflanguage dysfunction in Alzheimer’s disease [52
&
].Most tDCS studies applied stimulation to
patients while they were awake, but one study exam-ined slow oscillatory tDCS delivered during a day-time nap [44
&&
]. Four of the tDCS studies includedcognitive training either before or during brainstimulation, with the intent to use brain stimulationto potentiate the effects of task-specific learning[46,47
&&
,52&
,53&
]. Out of 12 studies, three employeda separate sham control [42
&&
,43&
,47&&
], and threeemployed sham in a crossover design [44
&&
,46,52&
].Electrode localization exclusively used scalp land-marks; no studies used neuronavigation or model-ing to target stimulation. Brain regions targetedincluded either bilateral or unilateral prefrontalcortex or temporal lobe.
A variety of neuropsychiatric outcomes weremeasured across studies, including global cognition,verbal memory, visual memory, subjective memory,and language. Overall, results suggested a potentialfor boosting cognitive function using tES, but results
Copyright © 2019 Wolters Kluwe
1350-7540 Copyright � 2019 Wolters Kluwer Health, Inc. All rights rese
were mixed as to whether tES demonstrated statisti-cally significantly superiority compared to sham.
DISCUSSION
This review found an ongoing, robust interest in theapplication of NIBS to ADRD, spanning a range ofdisease severity. Since our previous review capturingdata until 2016 [7], there have been 12 new random-ized-controlled trials or proof-of-principle studies,and 8 new case reports or clinical case series, repre-senting a combined 244 ADRD patients studied.Results were encouraging for the use of NIBS toimprove global cognition and memory measuresin patients with a clinical diagnosis of Alzheimer’sdisease. However, widespread adoption of NIBS as astandard course of treatment remains hindered by anumber of methodological challenges, includingthe lack of clear consensus regarding optimal stim-ulation parameters, with variability seen in the type,intensity, frequency, location, and duration of stim-ulation. In the future, studies with larger numbers ofparticipants, rigorous blinding and sham proce-dures, and biomarker-confirmation of Alzheimer’sdisease diagnosis are needed to validate whetherNIBS techniques are useful as primary or adjuncttreatments for ADRD. In the following paragraphs,we summarize and discuss the strengths and limi-tations of the state-of-the-field in several key areas.
Patient characterization
Great strides have been made in developing in vivobiomarkers of Alzheimer’s disease pathophysiology,chiefly, tests for b-amyloid and tau proteins in theCSF or on positron emission tomography imaging.The recent National Institute of Aging – Alzheimer’sAssociation (NIA-AA) research framework proposedby Jack et al. [54] promotes a biomarker-based defi-nition of Alzheimer’s disease in vivo, allowing forstandardization of diagnostic criteria for use in inter-ventional research and biomarker studies. Whetherbecause of cost, risk, limited access, or a combina-tion of these factors, only a few studies in our reviewconfirmed Alzheimer’s disease pathology usingavailable biomarkers, and none demonstrated alter-ation of underlying disease pathogenesis. Instead,most studied relied on probable diagnostic criteriabased on clinical and neuropsychological evalua-tions. The lack of thorough characterization ofpatients invites unknown heterogeneity, which inturn increases the risk of Type II (or false-negative)errors. Improvements in diagnostic characterizationof patients will also facilitate the search for inter-ventions for different variants of Alzheimer’sdisease, dementias of non-Alzheimer’s disease
r Health, Inc. All rights reserved.
rved. www.co-neurology.com 297
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Tab
le2
.St
udie
sin
vest
igat
ing
tran
scra
nial
elec
tric
alst
imul
atio
nas
ath
erap
eutic
tool
inA
DRD
Elec
tric
al
stim
ula
tio
n
stu
die
s2
01
6-2
01
8
(ref
eren
ces)
Cri
teri
afo
r
AD
/MC
I(d
isea
se
sta
ge)
No
.o
fp
art
ici-
pa
nts
Typ
eo
f
stim
ula
tio
n
Sha
m/
cont
rol
Inte
rlea
ved
cog
niti
ve
stim
ula
tio
n
Ag
e(m
ean
�SD
)
Targ
eta
rea
;lo
caliz
ati
on
met
hod
Sca
lp
elec
tro
de
1
Sca
lp
elec
tro
de
2
Sca
lpel
ectr
od
e
size
(cm
2)
Extr
acr
ani
al
elec
tro
de
and
size
(cm
2)
Cu
rren
t
Du
rati
on
(min
)
Tota
lnu
mb
ero
fse
ssio
ns;
leng
th
of
inte
rven
tio
n
Co
gni
tive
do
ma
in
Neu
rop
sych
o-
log
ica
lte
sts
–
pri
ma
ry
ou
tco
me
Neu
rop
sy-
cho
log
ica
l
test
s–
seco
nda
ry
ou
tco
mes
Ma
in
sig
nifi
cant
neu
rop
sych
o-
log
ica
l
find
ing
s
Pilo
tstu
dies
and
RCTs
[42&
&
]Pr
obab
leA
Dw
ith
incr
ease
dle
vel
ofce
rtain
tyby
NIN
CD
S-
AD
RDA
;M
MSE
>18
25
tDC
S;aw
ake
1:1
treat
men
t:
sham
No
Trea
tmen
t
gro
upag
e¼70.0�
8.0
;
sham
gro
up
age¼
75.0�
8.7
Lte
mpo
ral
lobe
;10-2
0
syst
em
Ano
de¼
T3C
atho
de¼
Fp2
35
Non
e2
mA
30
Six
sess
ions
;
10
days
Ver
bal
mem
ory
CV
LT-II
MM
SE,
TMT
A,
TMT
B,
cloc
k-
draw
ing
test
No
signi
fican
t
diffe
renc
esin
CV
LT-II
,M
MSE
,
TMT
A,
TMT
B,
orcl
ock
draw
ing
test
wer
ese
en
betw
een
the
treat
men
tand
sham
gro
up
[43&
]M
CId
iagno
sis
by
Pete
rson
crite
ria
16
tDC
S;aw
ake
1:1
treat
men
t:
sham
No
Trea
tmen
tgro
up
age¼
74.8�
7.5
;
sham
gro
up
age¼
73.1
�4.2
Bila
tera
l
DLP
FC;
10
–20
syst
em
Ano
de¼
F3C
atho
de
¼F4
25
Non
e2
mA
30
Nin
ese
ssio
ns;
3
wee
ks
Subj
ectiv
e
Mem
ory
Com
plai
nt
Scal
efrom
parti
cipa
nts,
FDG
-PET
MM
Qn/
aTh
etre
atm
entgro
up
show
ed
impr
ovem
enti
n
subj
ectiv
e
mem
ory
scor
es
onth
eM
MQ
-A
(abi
lity)
and
MM
Q-C
(con
tent
men
t)
subs
core
s
com
pare
dto
sham
[44&
&
]A
mne
stic
MC
I
(sin
gle
orm
ultid
omai
n)
bym
ayo
crite
ria,
with
obje
ctiv
e
cogni
tive
decl
ine
with
scor
es<
1SD
belo
wno
rms
on
mem
ory
test
s;
MM
SE�
24
16
Slow
osci
llato
ry
tDC
S;
deliv
ered
during
a
dayt
ime
nap
Bala
nced
cros
sove
r
desi
gn,
each
parti
cipa
nt
rece
ived
one
treat
men
t
and
one
sham
sess
ion,
at
leas
t
2w
eeks
apar
t
No
Age¼
71�
9Bi
fron
tal
stim
ulat
ion,
usin
gan
odal
curr
entw
ith
sinu
soid
al
osci
llatio
nsat
a
freq
uenc
yof
0.7
5H
z;10
–
20
syst
em
F3F4
0.6
4Bi
late
ral
mas
toid
s;
0.6
4
0.5
22
mA
/
cm2
...
15
–25
(5m
inbl
ocks
ofst
imul
atio
n
giv
endu
ring
stag
e2,3
,
or4
NRE
M
slee
p,fo
r
ato
talo
f
3–5
bloc
ks)
One
sess
ion;
1da
y
Vis
ual
reco
gni
tion
mem
ory,
EEG
Vis
uosp
atia
l
mem
ory
task
com
pris
edon
neut
ral
pict
ures
take
n
from
the
Inte
rnat
iona
l
Affe
ctiv
e
Pict
ure
System
Proc
edur
al
finge
r-
tapp
ing
task
,ve
rbal
mem
ory
task
,
loca
tion
mem
ory
task
Ther
ew
asan
impr
ovem
enti
n
visu
alre
cogni
tion
mem
ory
inth
e
treat
men
tgro
up
com
pare
dto
sham
whe
n
cont
rolli
ngfo
r
slee
pine
ss.
Ther
e
was
noef
fect
of
treat
men
ton
proc
edur
al
mem
ory,
verb
al
mem
ory,
or
loca
tion
mem
ory
[45&
]M
CId
iagno
sis
by
NIA
-AA
crite
ria,
CD
R¼
0.5
11
tDC
S;aw
ake
Non
eN
oA
ge¼
59.6
LD
LPFC
;10
–
20
syst
em
Ano
de¼
F3-F
P1
Cat
hode¼
R
supr
a-or
bita
l
regio
n
35
Non
e2
mA
20
Five
sess
ions
;
5da
ys
Vis
ual
mem
ory
PMIT
n/a
Impr
oved
imm
edia
te
and
dela
yed
reca
llon
the
PMIT
imm
edia
tely
afte
rco
nclu
sion
ofth
etre
atm
ent.
Impr
ovem
ento
n
dela
yed
reca
ll
PMIT
pers
iste
d
1m
onth
late
r
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Tab
le2
(Con
tinue
d)
Elec
tric
al
stim
ula
tio
n
stu
die
s
20
16
-20
18
(ref
eren
ces)
Cri
teri
afo
r
AD
/MC
I
(dis
ease
sta
ge)
No
.o
f
pa
rtic
i-p
ant
sTy
pe
of
stim
ula
tio
nSh
am
/co
ntro
l
Inte
rlea
ved
cog
niti
vest
imu
lati
on
Ag
e
(mea
n�
SD)
Targ
eta
rea
;
loca
liza
tio
nm
etho
dSc
alp
elec
tro
de
1Sc
alp
elec
tro
de
2
Sca
lp
elec
tro
de
size
(cm
2)
Extr
acr
ani
al
elec
tro
de
and
size
(cm
2)
Cu
rren
tD
ura
tio
n(m
in)
Tota
lnu
mb
ero
f
sess
ions
;le
ngth
of
inte
rven
tio
nC
og
niti
ved
om
ain
Neu
rop
sych
o-
log
ica
lte
sts
–
pri
ma
ryo
utc
om
e
Neu
rop
sy-
cho
log
ica
l
test
s–
seco
nda
ryo
utc
om
es
Ma
insi
gni
fica
nt
neu
rop
sych
o-
log
ica
lfi
ndin
gs
[46]
MC
Idia
gno
sis
by
mod
ified
Pete
rson
’s
crite
ria,
MO
CA
19
–26,
CD
R
�0.5
5tD
CS; aw
ake
A-B
-C-A
prot
ocol
;
anod
al
tDC
Sþ
CS,
sham
tDC
Sþ
CS,
and
CS
only
Yes
Age¼
72.8
�6.6
LD
LPFC
;
10
–20
syst
em
Ano
de¼
LD
LPFC
n/a
35
Rde
ltoid
;
35
2m
A30
One
tofiv
e
sess
ions
tota
l
ofac
tive
tDC
Sþ
cogni
tive
stim
ulat
ion
Not
spec
ified
Not
spec
ified
Pref
orm
ance
on
cogn
itive
stim
ulat
ion
task
sfro
m
neur
onU
p,
MO
CA
,
digi
tspa
n,
TMT
Som
epa
rtici
pant
s
show
ed
impr
ovem
ento
n
seve
ralm
easu
res,
butn
ost
atis
tical
ly
signi
fican
t
conc
lusi
ons
can
bedr
awn
[47&&
]A
mne
stic
MC
Iby
Pete
rson
crite
ria,
MM
SE24
–30,
CD
R¼
0.5
18
tDC
S;aw
ake
1:1
treat
men
t:
sham
Yes
Trea
tmen
tgro
up
age¼
75.3�
4.8
;sh
am
gro
up
age¼
75.3
�2.2
Lla
tera
l
pref
ront
al
corte
x;
10
–20
syst
em
Ano
de¼
F3C
atho
de
¼Fp
2
35
n/a
1.5
mA
15
Day
1¼
initi
al
lear
ning
sess
ion
only
,da
y
2¼
mem
ory
reac
tivat
ion
þac
tive
tDC
Sor
sham
sess
ion,
day
3an
dda
y30
¼re
triev
alse
ssio
n
only
Ver
bal
mem
ory
Expe
rim
enta
l
mem
ory
task
(lear
ning
,
reac
tivat
ion,
free
reca
ll,
and
reco
gni
tion)
n/a
Act
ive
tDC
S
treat
men
t
enha
nced
Mem
ory
Reco
gni
tion
scor
esco
mpa
red
tosh
am
Cas
ere
ports
and
clin
ical
case
series
[48]
AD
diag
nosi
sby
NIN
CD
S-
AD
RDA
crite
ria,
CD
R¼
1
1tD
CS;
awak
eN
one
No
Age¼
73
LD
LPFC
;
10
–20
syst
em
Ano
de ¼F3
Cat
hode¼
R
supr
aorb
ital
regio
n
35
n/a
2m
A30
10
sess
ions
;
2w
eeks
Glo
bal
cogni
tion
AD
AS-
Cog
NPI
,BD
S,
DA
D
Afte
rtre
atm
ent,
AD
AS-
Cog
,N
PI,
BDS,
and
DA
D
show
ed
impr
ovem
ent
com
pare
dto
base
line
[49]
Early
AD
diag
nosi
s,
crite
ria
not
spec
ified
1tD
CS;
awak
eN
one
No
Age¼
59
Lte
mpo
ral
lobe
;
10
–20
syst
em
Ano
de¼
T3C
atho
de¼
FP2
Not
spec
ified
n/a
2m
A30
12
sess
ions
;
6da
ys
Ver
bal
mem
ory
CV
LT-II
,EE
GM
MSE
,TM
T
A,
D-K
EFS
Wor
d
Flue
ncy,
WM
S
Atte
ntio
n
span
,
cloc
k-
draw
ing
test
Afte
rtre
atm
ent,
the
CV
LT-II
and
MM
SEsh
owed
impr
ovem
ent
com
pare
dto
base
line
[50&
]Ea
rly-o
nset
AD
,
Dub
ois
crite
ria
1tD
CS;
awak
e,
appl
ied
at
hom
ew
ith
help
from
fam
ily
Non
eN
oA
ge¼
60
Lte
mpo
ral
lobe
;
10
–20
syst
em
Ano
de¼
T3C
atho
de
¼FP
2
Not
spec
ified
n/a
2m
A30
Dai
lyfo
r8
mon
ths
Mem
ory,
visu
ospa
tial,
lang
uage,
and
atte
ntio
n
RBA
NS
Ove
rall
the
patie
nt’s
cogni
tive
func
tion
rem
aine
dst
able
over
8m
onth
s,
with
impr
ovem
ent
inm
emor
y
(imm
edia
tean
d
dela
yed
reca
ll),
and
decl
ine
in
visu
ospa
tial
func
tion
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Tab
le2
(Con
tinue
d)
Elec
tric
al
stim
ula
tio
nst
ud
ies
20
16
-20
18
(ref
eren
ces)
Cri
teri
afo
rA
D/M
CI
(dis
ease
sta
ge)
No
.o
f
pa
rtic
i-
pa
nts
Typ
eo
f
stim
ula
tio
n
Sha
m/
cont
rol
Inte
rlea
ved
cog
niti
ve
stim
ula
tio
n
Ag
e
(mea
n
�SD
)
Targ
eta
rea
;
loca
liza
tio
n
met
hod
Sca
lp
elec
tro
de
1
Sca
lp
elec
tro
de
2
Sca
lp
elec
tro
de
size
(cm
2)
Extr
acr
ani
al
elec
tro
de
and
size
(cm
2)
Cu
rren
t
Du
rati
on
(min
)
Tota
lnu
mb
ero
f
sess
ions
;le
ngth
of
inte
rven
tio
n
Co
gni
tive
do
ma
in
Neu
rop
sych
o-
log
ica
lte
sts
–
pri
ma
ry
ou
tco
me
Neu
rop
sy-
cho
log
ica
lte
sts
–
seco
nda
ry
ou
tco
mes
Ma
in
sig
nifi
cant
neu
rop
sych
o-
log
ica
l
find
ing
s
[52&
]Po
ssib
leA
D
diag
nosi
sby
NIN
CD
S-
AD
RDA
crite
ria,
MM
SE¼
14.2
7
1tD
CS;
awak
eO
new
eek
of
sham
was
follo
wed
by treat
men
t
inte
rven
tion
Yes
Age¼
67
Ran
gul
ar
and
supr
amar
gin
al
gyr
us;
10
–20
syst
em
Ano
de¼
P6-C
P6
Cat
hode¼
L
supr
aorb
ital
regio
n
35
n/a
2m
A30
five
sess
ions
;
1w
eek
Lang
uage
BAD
AA
fter tre
atm
ent
ther
ew
asa
signi
fican
t
impr
ovem
enti
n
com
preh
ensi
on
ofve
rbs,
com
pare
dto
sham
.Th
is
pers
iste
dfo
r
2w
eeks
post
stim
ulat
ion.
[53&
]Po
ster
ior
corti
cal
atro
phy
with
AD
diag
nosi
svi
a
CSF
tau
and
a-b
1tD
CS;
awak
eN
one
Cog
nitiv
e
reha
bth
erap
y
pref
orm
ed
prio
rto
initi
atio
n
oftD
CS
Age¼
58
LD
LPFC
;
10
–20
syst
em
Ano
de ¼F3
n/a
Not
spec
ified
Rsh
ould
er2
mA
20
20
sess
ions
;4
wee
ks;
repe
ated
for
two
sepa
rate
cycl
es,
tota
lof40
tDC
Sse
ssio
ns
Exec
utiv
e
func
tion,
fMRI
Stro
op task
whi
le
inth
efM
RI
scan
ner
Com
plet
e
NPS
eval
uatio
n
The
patie
ntsh
owed
impr
ovem
ento
n
the
Stro
opta
sk
afte
rco
gni
tive
train
ing,
whi
ch
was
mai
ntai
ned
afte
rth
efir
stan
d
seco
ndtD
CS
cycl
e
[51&
]O
nepa
tient
with
anA
D
diag
nosi
s,on
e
patie
ntw
itha
LBD
diag
nosi
s
2H
igh
defin
ition
tDC
S;
awak
e
Non
eN
oA
Dpa
tient
age
¼;
LBD
patie
nt
age¼
68
10
–10
syst
em
Hig
h defin
ition
tDC
Sus
ed
five
ring
elec
trode
s
arra
nged
on
the
scal
p
arou
ndth
e
cent
ral
Cat
hode
Cat
hode
¼C
P5
Ring
elec
trode
s
with
oute
r
radi
us
12
mm
,
inne
r
radi
us6
mm
n/a
2m
A20
Two
sess
ions
per
day,
10
–
20
sess
ions
tota
l;
5–10
days
of
treat
men
t
Aud
itory
hallu
cina
tions
AH
RSBo
thth
eA
Dan
d
LBD
patie
nt
show
edde
crea
se
freq
uenc
yof
audi
tory
hallu
cina
tions
on
the
AH
RSan
d
decr
ease
dac
ting
outb
ehav
ior
Stud
ies
inve
stig
atin
gtE
Sfo
rtre
atm
entof
Alz
heim
er’s
dise
ase
and
rela
ted
dem
entia
sus
ing
clin
ical
orbi
omar
ker
diag
nost
iccr
iteria.
Age
issh
own
asm
ean�
SD.
AD
,A
lzhe
imer
’sdi
seas
e;A
DA
S-C
og,
Alz
heim
er’s
Dis
ease
Ass
essm
entSc
ale-
cogni
tive;
AH
RS,
Aud
itory
Hal
luci
natio
nsRa
ting
Scal
e;BA
DA
,Ba
ttery
for
the
Ana
lysi
sof
the
Aph
asic
Def
icit;
BDS,
Bles
sed
Dem
entia
Scal
e;C
DR,
clin
ical
dem
entia
ratin
g;
CV
LT,
Cal
iforn
iaV
erba
lLea
rnin
gTe
st;
CSF
,ce
rebr
alsp
inal
fluid
;D
AD
,D
isab
ility
Ass
essm
entfo
rD
emen
tia;
D-K
EFS,
Del
is-K
apla
nEx
ecut
ive
Func
tion
Syst
em;
DLP
FC,
dors
olat
eral
pref
ront
alco
rtex;
FDG
-PET
,flu
orod
eoxy
glu
cose
posi
tron
emis
sion
tom
ogra
phy;
EEG
,el
ectro
ence
phal
ogra
phy
;LB
D,
Lew
ybo
dyde
men
tia;
LD
LPFC
,le
ftdo
rsol
ater
alpr
efro
ntal
corte
x;M
CI,
mild
cogni
tive
impa
irm
ent;
MM
Q,
Mul
tifac
torial
Mem
ory
Que
stio
nnai
re;
MM
SE,
Min
i-Men
talS
tate
Exam
inat
ion;
MO
CA
,M
ontre
alC
ogni
tive
Ass
essm
ent;
NIA
-AA
,N
atio
nalI
nstit
ute
ofA
gin
g–
Alz
heim
er’s
Ass
ocia
tion;
NIN
CD
S,N
atio
nalI
nstit
ute
ofN
euro
logic
alan
dC
omm
unic
ativ
eD
isor
ders
and
Stro
ke;
NPI
,N
euro
psyc
hiat
ric
Inve
ntor
y;N
REM
,no
n-ra
pid
eye
mov
emen
t;PM
IT,
Pict
ure
Mem
ory
Impa
irm
entTe
st;
RBA
NS,
Repe
atab
leBa
ttery
for
the
Ass
essm
entof
Neu
rops
ycho
logic
alSt
atus
;RC
Ts,
rand
omiz
edco
ntro
lled
trial
s;tD
CS,
trans
cran
ialdi
rect
curr
entst
imul
atio
n;tE
S,tra
nscr
ania
lele
ctrica
lst
imul
atio
n;TM
T,Tr
ailM
akin
gTe
st;
TMT
A,
trail
mak
ing
test
,pa
rt-A
;TM
TB,
trail
mak
ing
test
,pa
rt-B;
WM
S,W
echs
ler
Mem
ory
Scal
e.
Noninvasive brain stimulation in Alzheimer’s disease Buss et al.
etiologies, and preclinical/prodromal populations(for recent meta-analyses, see [55,56]). Attemptshave been made to improve information aboutand access to Alzheimer’s disease biomarkertest, including the recently completed ImagingDementia – Evidence for Amyloid Scanning study(ClinicalTrials.gov: NCT02420756). In the future,we recommend a biomarker-based approach tostudy participant inclusion in NIBS treatment trials,to confirm disease pathology and assure translatabil-ity to clinical populations.
Study design and use of sham/placebo
Small pilot studies were the most common encoun-tered in the literature, followed by clinical reports.Publications of large, randomized, double-blinded,placebo-controlled clinical trials were lacking. Themajority of studies approached NIBS as a symptom-atic treatment, aimed at boosting specific domainsof cognitive function. More than a third of studiesemployed interleaved cognitive training or usedNIBS to boost or extend the effects of previouslyperformed cognitive rehabilitation.
Our review found no large-scale studies demon-strating superiority of NIBS treatments compared tosham stimulation. Recently, there has been a resur-gence of interest in the placebo effect and its impli-cations for clinical research (for a review, see [57]).This is particularly relevant to NIBS, in which appro-priate blinding is difficult to obtain because of theoccurrence of robust peripheral (auditory, somato-sensory, and motor) effects that accompany TMSpulses or the ramping of tES currents. Cross-overdesigns offer additional challenges given potentialcarry-over and long-lasting effects, as well as intra-individual variability of NIBS [58] coupled withinterindividual or disease-specific differences inexpectation and memory, which can result in effectsthat are difficult to interpret. These challenges maybe especially problematic in ADRD given thatpatients may not spontaneously report or recallprior experiences making assessment of blindingsuccess and expected outcomes difficult. In thefuture, we recommend rigorous sham-control pro-cedures without a crossover design, inclusion ofonly NIBS-naıve participants, and poststudy assess-ment of blinding by both Alzheimer’s diseaseparticipants and their study partners (who may beproviding information regarding functional patientoutcomes).
Identification of target(s)
With the opportunity to target specific brainregions and networks, NIBS shows potential for
Copyright © 2019 Wolters Kluwe
1350-7540 Copyright � 2019 Wolters Kluwer Health, Inc. All rights rese
symptomatic treatment of Alzheimer’s disease-related cognitive decline in global cognition orwithin specific domains such as memory, language,attention, or motivation. Although brain stimula-tion sites varied across studies, the rationale fortarget sites was generally based on neuroanatomicalcorrelates of cognitive dysfunction in Alzheimer’sdisease. Studies using TMS were able to target corti-cal regions with greater focality and using MRIguidance, and frequently stimulated brain targetsknown to be strongly involved in Alzheimer’s dis-ease pathogenesis, including the six brain regionsadapted from the NeuroAD trial. Knowledge of dis-tributed resting state networks also played a role inthe choice of stimulation site, with one study usingthe precuneus as a TMS target because of connectiv-ity with the default mode network [40
&&
]. Severalstudies used tES to target symptoms of Alzheimer’sdisease such as memory, apathy, language dysfunc-tion, or auditory hallucinations. Another tES appli-cation used slow oscillatory tDCS during a daytimenap, which aimed to increase the power of sleep-related slow oscillations and sleep spindles toimprove memory consolidation [44
&&
]. Althoughthe use of structural and functional neuroimagingcan improve the selection of targets for TMS and tES,a major limitation common to all reviewed studies isthe lack of appropriate neurophysiological markersto gauge target engagement and monitor response.Modeling of the induced electrical field can helpbridge this gap, though the future will undoubtedlyrequire the combination of NIBS with concurrentelectroencephalography, MRI, or positron emissiontomography imaging. Although a few basic researchstudies highlight the potential and feasibility ofthese combined approaches [59–61], they haveyet to be applied to clinical trials for ADRD andthere remain critical questions about methodology,analysis, and interpretation.
Temporal interference
A commonality across the NIBS techniques includedin this review is that their targets are largelyrestricted to superficial regions of cortex. Exceptionsto this rule do exist, namely, that the effects of TMSare polysynaptic and stimulation of deeper regions(such as the cingulate cortex) is possible with certaincoils such as the double-cone [62] or H-Coil [63].However, the physics of electromagnetic inductionstipulate that deeper permeation comes at theexpense of reduced focality. Similarly, some modelsof tDCS do suggest that the induced electrical fieldextends beyond superficial layers, though the effectsare always strongest directly adjacent to theelectrodes [64]. Given the prominent role of the
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rved. www.co-neurology.com 301
Degenerative and cognitive diseases
hippocampal formation and adjacent structures inAlzheimer’s disease pathology (or the basal gangliain Parkinson’s and Huntington’s diseases), the abil-ity to directly and selectively target deeper structureshas long been a challenging, aspirational goal forresearchers and practitioners of NIBS. This maychange with a tACS-based approach of temporallyinterfering electrical fields, or ‘temporal interfer-ence’ [65]. The principles of temporal interferencebear some resemblance to those of confocal micro-scopy, wherein two half-strength photons aredirected to collide and thus summate to excite adeeper structure. In temporal interference, twoultra-high frequency oscillations with small differ-ence (e.g., 10 000 Hz and 10 010 Hz) are directed intothe brain from opposing areas such that they ‘col-lide’ in some deep structure such as the hippocam-pus. Although the individual frequencies are toohigh to affect neural tissue, they summate by sub-traction, resulting in a stimulating frequency of thedifference (e.g., 10 Hz). To date, temporal interfer-ence has moved beyond modeling to animal studies,confirming the ability to selectively stimulatedeeper structures such as the hippocampus inrodents [65]. In the future, temporal interferencemay be translated to humans who have or are at riskof developing ADRD [66], which would allow forimproved focality of stimulation on deep corticaltargets, including medial limbic structures.
Gamma oscillations
Although the studies to date have focused on the useof NIBS to enhance neural activity related to cogni-tion, there is preliminary evidence to suggest thattACS may be able to decrease amyloid deposits in thebrain. Working with a mouse model of Alzheimer’sdisease, Iaccarino et al. [67] demonstrated that usingoptogenetics to entrain fast-spiking parvalbumin-positive interneurons at 40 Hz (i.e., gamma fre-quency) reduced levels of amyloid-b (Ab)1-40 andAb1-42 isoforms. In theory, tACS could achievea similar effect in humans. Indeed, there is anongoing open-label proof-of-principle study to testthe efficacy of daily 1-h sessions of 40 Hz tACS(ClinicalTrials.gov: NCT03290326). Further studyis needed to determine whether this approachcan lead to a lasting alteration of electrographiccortical rhythms, interact with proteins involvedin neurodegeneration, or lead to meaningful clinicalimprovement in ADRD.
CONCLUSION
NIBS remains an active area of investigation fortreatment of ADRD, though the predominance of
Copyright © 2019 Wolters Kluwer H
302 www.co-neurology.com
small, heterogeneous, proof-of-principle studiesprecludes definitive conclusions. There is currentlyinsufficient evidence to support widespread adop-tion of NIBS-based clinical treatments for ADRD,but promising results should encourage continuedinvestigation. The future of NIBS as a therapeuticintervention for ADRD will depend on overcomingthree major obstacles: the standardization of NIBSstimulation parameters, confirmation of targetengagement, and the recruitment of large, well-characterized cohorts with a biomarker-confirmeddiagnosis with sufficient longitudinal follow-up.Addressing all of these challenges is a high bar tocross for any individual research laboratory or cen-ter, though a failure to do so will keep the field miredin small, heterogeneous, proof-of-principle studiesand case reports lacking in scientific rigor. We there-for propose the establishment of a large-scale, pos-sibly international, consortium, with collaborationbetween academia and industry. Based on the suc-cessful model of the Alzheimer’s Disease Neuroim-aging Initiative [68], methodological parametersshould be published in advance and data collectedfrom this consortium should be placed in a reposi-tory and made available to independent researchers.
Acknowledgements
None.
Financial support and sponsorship
This work was primarily supported by grants from theNational Institutes of Health (NIH; 3R01MH115949-01S1 and R21AG051846). S.S.B. was further supportedby the Sidney R. Baer Jr. Foundation (01028951) andNeuroNEXT. A.P.L. was also supported by the Sidney R.Baer, Jr. Foundation, Harvard Catalyst j The HarvardClinical and Translational Science Center (NCRR andthe NCATS NIH, UL1 RR025758), the Football PlayersHealth Study at Harvard University, and by the DefenseAdvanced Research Projects Agency (DARPA) viaHR001117S0030. The content is solely the responsibilityof the authors and does not necessarily represent theofficial views of Harvard Catalyst, Harvard Universityand its affiliated academic healthcare centers, theNational Institutes of Health, NeuroNEXT, the SidneyR. Baer Jr. Foundation, The Football Players HealthStudy, or DARPA.
A.P.L. serves on the scientific advisory boards forStarlab Neuroscience, Neuroelectrics, NeoSync, NovaVi-sion, and Cognito, and is listed as an inventor on severalissued and pending patents on the real-time integrationof transcranial magnetic stimulation with electroenceph-alography and magnetic resonance imaging.
Conflicts of interest
There are no conflicts of interest.
ealth, Inc. All rights reserved.
Volume 32 � Number 2 � April 2019
Noninvasive brain stimulation in Alzheimer’s disease Buss et al.
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27. Babiloni C, Lizio R, Marzano N, et al. Brain neural synchronization andfunctional coupling in Alzheimer’s disease as revealed by resting stateEEG rhythms. Int J Psychophysiol 2016; 103:88–102.
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34.&
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This study used interleaved cognitive training with a multisite rTMS adapted fromthe NeuroAD, and is notable in that it showed an improvement in the primaryoutcome of global cognition immediately after treatment, but not persisting at6 month follow-up.35.&&
Lee J, Choi BH, Oh E, et al. Treatment of Alzheimer’s disease with repetitivetranscranial magnetic stimulation combined with cognitive training: a pro-spective, randomized, double-blind, placebo-controlled study. J Clin Neurol2016; 12:57–64.
This study is notable as it is one of the few high-quality randomized control trials,including a sham control without crossover design and MRI guidance to targetbrain stimulation sites. This study illustrates the ongoing interest in validatingcommonly used protocols vs. sham controls, which is important given the issueswith blinding and placebo effect inherent in NIBS.36. Zhao J, Li Z, Cong Y, et al. Repetitive transcranial magnetic stimulation
improves cognitive function of Alzheimer’s disease patients. Oncotarget2017; 8:33864–33871.
37.&
Alcala-Lozano R, Morelos-Santana E, Cortes-Sotres JF, et al. Similar clinicalimprovement and maintenance after rTMS at 5 Hz using a simple vs. complexprotocol in Alzheimer’s disease. Brain Stimul 2018; 11:625–627.
This study is notable for comparing two different TMS treatment protocols, which isimportant to begin to standardize and draw comparisons across stimulationprocedures.38.&
Avirame K, Stehberg J, Todder D. Benefits of deep transcranial magneticstimulation in Alzheimer disease: case series. J ECT 2016; 32:127–133.
This study was the only in this review which used deep TMS to target the prefrontalcortex, which allows for deeper tissue penetration but reduced focality of stimulation.39.&
Rabey JM, Dobronevsky E. Repetitive transcranial magnetic stimulation(rTMS) combined with cognitive training is a safe and effective modalityfor the treatment of Alzheimer’s disease: clinical experience. J Neural Transm(Vienna) 2016; 123:1449–1455.
This report of clinical experiences in a private clinic offering commercial NeuroADtreatments shows that the ongoing interest in the off-label use of TMS treatments inADRD.40.&&
Koch G, Bonnı S, Pellicciari MC, et al. Transcranial magnetic stimulation of theprecuneus enhances memory and neural activity in prodromal Alzheimer’sdisease. Neuroimage 2018; 169:302–311.
This study is particularly notable because it is one of the few that used availablebiomarkers to confirm the diagnosis of prodromal Alzheimer’s disease andattempted to show a neurophysiological effect of the treatment.41.&
Padala PR, Padala KP, Lensing SY, et al. Repetitive transcranial magneticstimulation for apathy in mild cognitive impairment: a double-blind, rando-mized, sham-controlled, cross-over pilot study. Psychiatry Res 2018;261:312–318.
This study used a stimulation paradigm similar to rTMS treatment for depression totarget apathy in MCI, showing the importance of choosing stimulation targetsbased on known neuroanatomical correlates of cognitive symptoms.42.&&
Bystad M, Grønli O, Rasmussen ID, et al. Transcranial direct current stimula-tion as a memory enhancer in patients with Alzheimer’s disease: a randomized,placebo-controlled trial. Alzheimers Res Ther 2016; 8:13.
This study is notable as it was well designed and executed and reported a nullfinding on the effect of tDCS on verbal memory in Alzheimer’s disease.43.&
Yun K, Song I-U, Chung Y-A. Changes in cerebral glucose metabolism after3 weeks of noninvasive electrical stimulation of mild cognitive impairmentpatients. Alzheimers Res Ther 2016; 8:49.
This study used tDCS vs. sham control to target subjective memory, reflectingmemory satisfaction, and memory strategies of participants.44.&&
Ladenbauer J, Ladenbauer J, K€ulzow N, et al. Promoting sleep oscillations andtheir functional coupling by transcranial stimulation enhances memory con-solidation in mild cognitive impairment. J Neurosci 2017; 37:7111–7124.
This study is notable as it investigated a unique application of slow-oscillatorytDCS during a daytime nap to improve memory consolidation.
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Degenerative and cognitive diseases
45.&
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This study investigated the Picture Memory Impairment Test, which is a memoryinstrument with low educational bias; further investigations using this test couldincrease the translatability of NIBS techniques into a wider diversity of clinicalsettings.46. Cruz Gonzalez P, Fong KN, Brown T. The effects of transcranial direct current
stimulation on the cognitive functions in older adults with Mild cognitiveimpairment: a pilot study. Behav Neurol 2018; 2018:5971385.
47.&&
Manenti R, Sandrini M, Gobbi E, et al. Effects of transcranial direct currentstimulation on episodic memory in amnestic mild cognitive impairment: a pilotstudy. J Gerontol B Psychol Sci Soc Sci 2018. doi:10.1093/geronb/gby134.
This study measured whether tDCS was superior to sham in enhancing memoryconsolidation, and showed an improvement specifically in Recognition scores inthe treatment group, suggesting improvement in amnestic memory deficits relatedto Alzheimer’s disease.48. Andrade SM, de Mendonca CT, Pereira TC, et al. Adjuvant transcranial direct
current stimulation for treating Alzheimer’s disease: a case study. DementNeuropsychol 2016; 10:156–159.
49. Bystad M, Rasmussen ID, Abeler K, Aslaksen PM. Accelerated transcranialdirect current stimulation in Alzheimer’s disease: a case study. Brain Stimul2016; 9:634–635.
50.&
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This case study used at-home treatment of tDCS applied by the patient withassistance from family members over a course of 8 months, suggesting that at-home therapy may be feasible and tolerable.51.&
Mukku SS, Selvaraj S, Parlikar R, et al. High-definition transcranial directcurrent stimulation (HD-tDCS) for auditory hallucinations in dementia: a caseseries. Asian J Psychiatr 2018; 37:102–105.
This case study investigated the use of high-definition tDCS using five anodalelectrodes arranged around a central cathode to treat auditory hallucinations.52.&
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This case study targeted language impairment in a patient with a diagnosis ofAlzheimer’s disease, and reflects the growing interest in using NIBS to targetspecific domains of cognitive function.53.&
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This case study investigated tDCS treatment in posterior cortical atrophy, anAlzheimer’s disease variant, using CSF biomarkers to confirm the diagnosis.
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54. Jack CR, Bennett DA, Blennow K, et al. NIA-AA research framework: towarda biological definition of Alzheimer’s disease. Alzheimers Dement 2018;14:535–562.
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58. Fried PJ, Jannati A, Davila-Perez P, Pascual-Leone A. Reproducibility of single-pulse, paired-pulse, and intermittent theta-burst TMS measures in healthyaging, type-2 diabetes, and Alzheimer’s disease. Front Aging Neurosci 2017;9:263.
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Volume 32 � Number 2 � April 2019