CO Therapeutic noninvasive brain stimulation in Alzheimer ... · PINION Therapeutic noninvasive brain stimulation in Alzheimer’s disease and related dementias Stephanie S. Bussa,,

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-Leone
Purpose 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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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

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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


2016. Flow diagram of literature search. AD, Alzheimer’sMCI, mild cognitive impairment; NIBS, noninvasive brainmentia; PPA, primary progressive aphasia; SCI, subjective


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


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.


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



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




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


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

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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



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




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



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.




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26. Antal A, Herrmann CS. Transcranial alternating current and random noisestimulation: possible mechanisms. Neural Plast 2016; 2016:3616807.



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.

28. Brem A-K, Almquist JN-F, Mansfield K, et al. Modulating fluid intelligenceperformance through combined cognitive training and brain stimulation.Neuropsychologia 2018; 118:107–114.

29. Benussi A, Di Lorenzo F, Dell’Era V, et al. Transcranial magnetic stimulationdistinguishes Alzheimer disease from frontotemporal dementia. Neurology2017. doi:10.1212/WNL.0000000000004232.

30. Padovani A, Benussi A, Cantoni V, et al. Diagnosis of mild cognitive impair-ment due to Alzheimer’s disease with transcranial magnetic stimulation.J Alzheimers Dis 2018; 65:221–230.

31. Motta C, Lorenzo FD, Ponzo V, et al. Transcranial magnetic stimulationpredicts cognitive decline in patients with Alzheimer’s disease. J NeurolNeurosurg Psychiatry 2018. doi:10.1136/jnnp-2017-317879.

32. Koch G, Di Lorenzo F, Bonnı S, et al. Impaired LTP- but not LTD-like corticalplasticity in Alzheimer’s disease patients. J Alzheimers Dis 2012; 31:593–599.

33. Di Lorenzo F, Ponzo V, Bonnı S, et al. LTP-like cortical plasticity is disrupted inAlzheimer’s disease patients independently from age of onset. Ann Neurol2016. doi:10.1002/ana.24695.

34.&

Nguyen J-P, Suarez A, Kemoun G, et al. Repetitive transcranial magneticstimulation combined with cognitive training for the treatment of Alzheimer’sdisease. Neurophysiol Clin 2017; 47:47–53.

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.



https://www.alz.org/documents_custom/2018-facts-and-figures.pdf

https://www.alz.org/documents_custom/2018-facts-and-figures.pdf


45.&

Murugaraja V, Shivakumar V, Sivakumar PT, et al. Clinical utility and tolerabilityof transcranial direct current stimulation in mild cognitive impairment. Asian JPsychiatr 2017; 30:135–140.

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.&

Bystad M, Rasmussen ID, Grønli O, Aslaksen PM. Can 8 months of dailytDCS application slow the cognitive decline in Alzheimer’s disease? A casestudy. Neurocase 2017; 23:146–148.

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.&

Costa V, Brighina F, Piccoli T, et al. Anodal transcranial direct currentstimulation over the right hemisphere improves auditory comprehension ina case of dementia. NeuroRehabilitation 2017; 41:567–575.

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.&

Gramegna LL, Evangelisti S, Testa C, et al. Cognitive rehabilitation andtranscranial direct current stimulation in a patient with posterior corticalatrophy: an fMRI study. Am J Case Rep 2018; 19:729–733.

This case study investigated tDCS treatment in posterior cortical atrophy, anAlzheimer’s disease variant, using CSF biomarkers to confirm the diagnosis.



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.

55. Xu Y, Qiu Z, Zhu J, et al. The modulation effect of noninvasive brain stimulationon cognitive function in patients with mild cognitive impairment: a systematicreview and meta-analysis of randomized controlled trials. BMC Neuroscience2019; 20:2.

56. Lawrence BJ, Gasson N, Bucks RS, et al. Cognitive training and noninvasivebrain stimulation for cognition in Parkinson’s disease: a meta-analysis. Neu-rorehabil Neural Repair 2017; 31:597–608.

57. Burke MJ, Kaptchuk TJ, Pascual-Leone A. Challenges of differential placeboeffects in contemporary medicine: the example of brain stimulation. AnnNeurol 2018. doi:10.1002/ana.25387.

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.

59. Canali P, Sferrazza Papa G, Casali AG, et al. Changes of cortical excitabilityas markers of antidepressant response in bipolar depression: preliminary dataobtained by combining transcranial magnetic stimulation (TMS) and electro-encephalography (EEG). Bipolar Disord 2014; 16:809–819.

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61. Bestmann S, Baudewig J, Siebner HR, et al. BOLD MRI responses torepetitive TMS over human dorsal premotor cortex. Neuroimage 2005;28:22–29.

62. Cai W, George JS, Chambers CD, et al. Stimulating deep cortical structureswith the batwing coil: how to determine the intensity for transcranial magneticstimulation using coil-cortex distance. J Neurosci Methods 2012; 204:238–241.

63. Roth Y, Pell GS, Chistyakov AV, et al. Motor cortex activation by H-coil andfigure-8 coil at different depths. Combined motor threshold and electric fielddistribution study. Clin Neurophysiol 2014; 125:336–343.

64. Huang Y, Parra LC. Can transcranial electric stimulation with multiple elec-trodes reach deep targets? Brain Stimulation 2019; 12:30–40.

65. Grossman N, Bono D, Dedic N, et al. Noninvasive deep brain stimulation viatemporally interfering electric fields. Cell 2017; 169:1029.e16–1041.e16.

66. Grossman N, Okun MS, Boyden ES. Translating temporal interference brainstimulation to treat neurological and psychiatric conditions. JAMA Neurol2018; 75:1307–1308.

67. Iaccarino HF, Singer AC, Martorell AJ, et al. Gamma frequency entrainmentattenuates amyloid load and modifies microglia. Nature 2016; 540:230–235.

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