neural bases of pharmacological treatment of nicotine dependence - insights from functional brain...

SYSTEMATIC REVIEW

Neural Bases of Pharmacological Treatment of NicotineDependence - Insights from Functional Brain Imaging:A Systematic Review

Henrique Soila Menossi • Anna E. Goudriaan • Cintia de Azevedo-Marques Perico •

Sergio Nicastri • Arthur Guerra de Andrade • Gilberto D’Elia •

Chiang-Shan R. Li • Joao Mauricio Castaldelli-Maia

Published online: 14 July 2013

� Springer International Publishing Switzerland 2013

Abstract

Background Nicotine dependence is difficult to treat, and

the biological mechanisms that are involved are not

entirely clear. There is an urgent need to develop better

drugs and more effective treatments for clinical practice. A

critical step towards accelerating progress in medication

development is to understand the neurobehavioral effects

of pharmacotherapies on clinical characteristics associated

with nicotine dependence.

Objectives This review sought to summarize the func-

tional magnetic resonance imaging (fMRI) literature on

smoking cessation with the aim to better understand the

neural processes underlying the effects of nicotinic and

non-nicotinic pharmacological smoking cessation treat-

ments on specific symptoms of nicotine dependence and

withdrawal.

Data Sources We conducted a search in Pubmed, Web of

Science and PsycINFO databases with the keywords

‘fMRI’ or ‘functional magnetic resonance imaging’ and

‘tobacco’ or ‘nicotine’ or ‘smok*’. The date of the most

recent search was May 2012.

Study Eligibility Criteria, Participants and Interven-

tions The original studies that were included were

those of smokers or nicotine-dependent individuals,

published in the English language, with pharmacological

treatment for nicotine dependence and use of fMRI with

blood oxygen level-dependent (BOLD) imaging or con-

tinuous arterial spin labelling (CASL). No date limit was

applied.

Study Appraisal and Synthesis Methods Two of the

authors read the abstracts of all studies found in the search

(n = 1,260). The inclusion and exclusion criteria were

applied, and 1,224 articles were excluded. In a second step,

the same authors read the remaining 36 studies. Nineteen

of the 36 articles were excluded. The results were tabulated

by the number of individuals and their mean age, the main

sample characteristics, smoking status, study type and

methodology, and the main fMRI findings.

Results Seventeen original fMRI studies involving phar-

macological treatment of smokers were selected. The

anterior and posterior cingulate cortex, medial and lateral

orbitofrontal cortex, ventral striatum, amygdala, thalamus

and insula are heavily involved in the maintenance of

smoking and nicotine withdrawal. The effects of vareni-

cline and bupropion in alleviating withdrawal symptoms

and decreasing smoking correlated with modulation of the

activities of these areas. Nicotine replacement therapy

seems to improve cognitive symptoms related to with-

drawal especially by modulating activities of the default-

network regions; however, nicotine replacement does not

necessarily alter the activities of neural circuits, such as the

H. S. Menossi � C. de Azevedo-Marques Perico �A. G. de Andrade � G. D’Elia � J. M. Castaldelli-Maia (&)

Disciplinas de Psiquiatria e Psicologia Medica da Faculdade de

Medicina do ABC, Av. Lauro Gomes, 2000 – Vila Sacadura

Cabral, Santo Andre, SP 09060-870, Brazil

e-mail: [email protected]

A. E. Goudriaan

Department of Psychiatry, Academic Medical Center,

University of Amsterdam, Amsterdam, The Netherlands

A. E. Goudriaan

Arkin Mental Health Care, Amsterdam, The Netherlands

S. Nicastri � A. G. de Andrade � J. M. Castaldelli-Maia

Department of Psychiatry, Medical School, Universidade

de Sao Paulo, Sao Paulo, SP, Brazil

C.-S. R. Li

Department of Psychiatry, Yale University,

New Haven, CT, USA

CNS Drugs (2013) 27:921–941

DOI 10.1007/s40263-013-0092-8

cingulate cortices, that are associated with nicotine

addiction.

Limitations The risk of bias in individual studies, and

across studies, was not assessed, and no method of han-

dling data and combining results of studies was carried out.

Most importantly, positron emission tomography (PET)

studies were not included in this review.

Conclusions and Implication of Key Findings fMRI

studies delineate brain systems that contribute to cognitive

deficits and reactivity to stimuli that generate the desire to

smoke. Nicotinic and non-nicotinic pharmacotherapy may

reduce smoking via distinct neural mechanisms of action.

These findings should contribute to the development of

new medications and discovery of early markers of the

therapeutic response of cigarette smokers.

1 Introduction

Tobacco use originated in the Americas thousands of years

ago and spread to the rest of the world over the past

500 years. Nowadays, smoking is a major public health

concern and is one of the most preventable causes of death

worldwide [1]. Approximately 1.3 billion people currently

smoke tobacco, most commonly in the form of cigarettes [1].

The number of smokers is growing, particularly in low- and

middle-income countries, where cigarettes are marketed

aggressively by some of the most powerful tobacco com-

panies in the world [1]. It is expected that by the year 2025,

there will be 1.6 billion smokers in the world [1]. The delay

between the onset of smoking and the manifestation of its

health impact is a key factor leading to the epidemic of

smoking. About half of all long-term smokers die of smok-

ing-related diseases, and half of these deaths occur during

middle adulthood, resulting in 20 to 25 years of life loss [1].

Nicotine dependence is difficult to treat. Only 5–7 % of

smokers who try to stop smoking without pharmacological

treatment remain abstinent for more than 6 months [2].

Retrospective studies have estimated that 2–15 % of

smokers relapse after the first year of abstinence [2]. There

is an urgent need to develop better and more effective

pharmacological aids for smoking cessation to be used in

clinical practice, as well as health policies to support public

access to these treatments [3, 4].

Chronic exposure to nicotine initiates neuroadaptation

and promotes continued tobacco use. When a smoker

attempts to stop, the neural homeostasis maintained by

chronic nicotine exposure is disrupted, leading to with-

drawal and manifestation of affective and somatic symp-

toms reflecting the neurochemical imbalance [5, 6].

However, the neural basis of this imbalance has remained

elusive, as a number of neurotransmitters, cognitive and

affective processes, and brain regions are involved [7].

The United States Food and Drug Administration (FDA)

and European Medicines Agency (EMA) have approved

some pharmacotherapies for the treatment of nicotine

dependence, such as varenicline (a partial agonist of neu-

ronal nicotinic acetylcholine receptors), bupropion (a

selective inhibitor of dopamine and noradrenaline re-

uptake), and nicotine replacement therapy (NRT) with

nicotine gum, nicotine lozenges, nicotine nasal spray and

transdermal nicotine patches. These medications increase

the odds of cessation success, compared with a placebo, in

people who want to quit smoking [4]. However, ongoing

research is expected to contribute to more efficacious use

of existing therapies, development of new approaches, and

study of medications approved for other indications (i.e.

baclofen) [4].

The biological mechanisms involved in nicotine

dependence are not entirely clear. A critical step towards

accelerating progress in development of pharmacological

therapy for smoking cessation is to understand the neuro-

behavioral effects of pharmacotherapies on clinical char-

acteristics associated with nicotine dependence [8, 9]. This

literature review aims to summarize the current knowledge

about neural processes underlying the actions of existing

pharmacotherapies for nicotine dependence.

2 Methods

2.1 Eligibility

Original studies of smokers or nicotine-dependent indi-

viduals, published in the English language, with pharma-

cological treatment of nicotine dependence and use of

functional magnetic resonance imaging (fMRI) with blood

oxygen level-dependent (BOLD) imaging or continuous

arterial spin labelling (CASL) were included in this review.

Excluded from this review were reviews; congress/meeting

abstracts; studies in languages other than English; studies

using animals; studies using other imaging modalities;

studies that analyzed the effect of nicotine through intra-

venous administration; studies of nicotinic drugs in non-

smokers; studies that analyzed only non-pharmacological

treatments of nicotine dependence; and studies that

examined other features unrelated to drug treatment of

nicotine dependence or other pathological conditions

unrelated to tobacco dependence.

2.2 Information Sources

We referred to the Pubmed database of the US National

Library of Medicine, Web of Science (EMBASE)

and PsycINFO on 5 May 2012 to identify relevant

studies.

922 H. S. Menossi et al.

2.3 Search

The keywords used in the search were (i) ‘fMRI’, ‘func-

tional magnetic resonance imaging’ and ‘tobacco’; (ii)

‘fMRI’, ‘functional magnetic resonance imaging’ and

‘nicotine’; and (iii) ‘fMRI’, ‘functional magnetic resonance

imaging’ and ‘smok*’.

2.4 Study Selection

To select articles for this review, the first and the last

author read the abstracts of all studies found in the search

(n = 1,260). The inclusion and exclusion criteria were

applied, and 1,224 articles were excluded. In a second step,

the first author read the remaining 36 studies. Nineteen of

the 36 articles were excluded because they employed or

studied combined electroencephalographic (EEG) and

fMRI recording (two articles); genotyping and fMRI (one

article); nicotine gum effects in non-smokers (six articles);

and only non-pharmacological treatments (ten articles).

A PRISMA [10] flow diagram is presented in Fig. 1.

2.5 Data Collection Process

The first and the last author read all of the 17 included

studies independently. The first author tabulated the data,

then the tabulated data were evaluated by the last author. In

cases of disagreement between the first and the last author

on the information to be presented in the review, a third co-

author made the decision as to the best way to present the

data.

2.6 Data Items

This review sought information on the following variables:

the number of individuals enrolled in the study and their

mean age, sample characteristics, smoking status, study

type and methodology, and the main fMRI findings related

to the pharmacological intervention. No methods of han-

dling data and combining results of studies were carried

out, for of two reasons. First, the vast majority of the

studies that were found were not randomized clinical trials,

and there were many differences in these studies’ designs.

In addition, these studies evaluated many different out-

comes, testing for effects in different brain areas.

3 Results

3.1 Non-nicotinic Pharmacological Treatments

Six studies involved non-nicotinic pharmacological treat-

ment (NNPT), with three employing BOLD fMRI (two

studies with varenicline, one study with bupropion) and

three studies employing CASL perfusion fMRI (one with

varenicline and two with baclofen). There were no fMRI

studies with nortriptyline, clonidine or other non-nicotinic

medications for smoking cessation. The main features of

these imaging studies are listed in Table 1. The neural

areas affected by non-nicotinic pharmacological agents are

summarized in Fig. 2.

3.1.1 Varenicline

In the present review, we found three fMRI studies

involving varenicline [11–13]. Two studies used BOLD,

and one study used CASL perfusion. In a double-blind

randomized controlled trial with 22 smokers who were not

seeking treatment [11], 11 patients were treated with va-

renicline, up to a final dose of 1 mg twice daily, and the

remainder were treated with a placebo. All individuals

were evaluated for craving by exposure to triggers related

to smoking and neutral stimuli (videos) and correlation of

craving with CASL perfusion fMRI. The fMRI procedure

was performed on the 1st and 21st days of the treatment.

Before each session, subjects smoked one cigarette of their

preferred brand. The Shiffman-Jarvik withdrawal scale

[14] was applied before and after exposure. In the first

fMRI session, exposure to smoking cues was associated

with activation in the ventral striatum and the medial

orbitofrontal cortex. There was an increase of craving in

both groups after exposure, and this correlated with

increased activity in the posterior cingulate cortex. In the

second fMRI session, during exposure to smoking cues,

administration of varenicline was associated with increased

activity in the anterior and posterior cingulate cortices, the

inferior, middle and upper frontal gyri, the lateral orbito-

frontal cortex and the dorsolateral prefrontal cortex. Fol-

lowing exposure to the triggers, the increased craving was

statistically significant only in the placebo group, and it

correlated with increased activity in the posterior cingulate

cortex and the medial orbitofrontal cortex, whereas such a

correlation was not present in the group who received va-

renicline. Analysis of neural activity at rest showed

increased activity associated with use of varenicline in the

bilateral orbitofrontal cortex. Increased activity in the right

lateral orbitofrontal cortex correlated with decreased

reactivity of the medial orbitofrontal cortex during pre-

sentation of triggers. A decrease in the activity of the right

amygdala and the posterior and dorsal insula was also

present during rest [11].

A double-blind study with 22 smokers seeking treatment

[12]—of whom ten received varenicline—examined the

neural mechanisms underlying the effects of medication on

cognitive impairment related to nicotine withdrawal.

Twenty-two smokers completed 13 days of varenicline and

fMRI Findings for Smoking Cessation Treatments 923

placebo treatment in a double-blind crossover study with

two fMRI sessions: after 3 days of abstinence while on

varenicline; and after 3 days of abstinence while on a

placebo (in a counterbalanced randomized order with a

2-week washout). BOLD fMRI data were acquired during

performance of a visual N-back working memory task.

Compared with the placebo, varenicline resulted in a faster

correct-response time only in severe nicotine-dependent

subjects, with a score of 6–10 on the Fagerstrom test for

nicotine dependence (FTND) scale. There was no effect on

the number of correct answers. The authors further found a

significant increase in the BOLD signal at higher levels of

task difficulty with the use of varenicline, as compared

with the placebo, in the dorsal anterior cingulate medial

frontal and bilateral dorsolateral prefrontal cortices [12].

A similar study with the same sample [13] evaluated the

effects of varenicline on emotional processing during

abstinence. Participants performed a task on the 13th day

of treatment to identify emotional expressions in faces.

Varenicline improved the correct-response time. However,

no effect was noted on the accuracy of performance (the

number of true positive responses) or on positive and

negative affect scores in the positive and negative affect

schedule (PANAS). Compared with the placebo, vareni-

cline was associated with a decrease in the BOLD signal in

the dorsal anterior cingulate cortex, medial frontal cortex,

occipital cortex and thalamus, and an increase in the tem-

poral gyrus without an effect on the modulation in the

BOLD signal by the kind of emotion. No significant effects

were observed in the amygdala in the first instance. How-

ever, with regions of interest analysis, a decrease was noted

in the signal that was not affected by the kind of emotion.

These results suggest that the drug effect on the BOLD

signal does not reflect affective changes. Nevertheless, it

briefly improves perceptual processing of facial stimuli

[13].

Fig. 1 Flow diagram following the PRISMA Group statement. EEG electroencephalogram, fMRI functional magnetic resonance imaging


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ativ

eaf

fect

sched

ule


Fig. 2 Neural areas affected by pharmacological treatment compared

with placebo in functional magnetic resonance imaging (fMRI)

studies. B BOLD fMRI technique, BAC baclofen, BUP bupropion,

C continuous arterial spin labelling perfusion fMRI technique,

NNPT non-nicotinic pharmacological treatment (black), NRT nicotine

replacement treatment (white), VAR varenicline


3.1.2 Bupropion

We found only one fMRI study involving bupropion—a

double-blind randomized controlled study with BOLD

fMRI [15]. Thirty participants were randomly assigned to

receive 8 weeks of treatment with either bupropion

(300 mg daily for 8 weeks) or a placebo. Participants

smoked their usual cigarette(s) in the morning and under-

went BOLD fMRI before and after treatment (participants

who quit smoking during the study were not required to

smoke prior to the second fMRI scan). Videos containing

first-person smoking and neutral scenes were shown. Each

scanning session consisted of three runs, each with neutral,

crave-allow and crave-resist cigarette cue videos. Self-

reported craving on an urge to smoke scale was assessed

during the scan. The group who received bupropion had

lower scores on the FTND scale and carbon monoxide

measures, and reported less desire to smoke after treatment,

with improved ability to resist cue-induced craving. How-

ever, there were no differences in cessation of smoking

between the two groups. Comparing the stimuli-evoked

desire to smoke pre- and post-treatment, participants treated

with bupropion as compared with the placebo had a sig-

nificantly greater reduction in activation in the left ventral

striatum, medial orbitofrontal cortex and right anterior

cingulate cortex bilaterally. There was also a correlation

between changes in self-reported desire with reduced

regional activation in the medial orbitofrontal cortex bilat-

erally and the left anterior cingulate cortex, in the pre and

post-treatment measures, for all participants [15].

Fig. 2 continued


3.1.3 Baclofen

We found two studies involving baclofen, both carried out

with CASL perfusion fMRI during the resting state [16,

17]. In a small, double-blind, randomized controlled trial

with 21 smokers [16]—10 participants on baclofen 20 mg

four times daily and 11 on a placebo—CASL perfusion

fMRI was performed during the resting state before and on

the first day after treatment. Before each session, the sub-

jects smoked freely. Use of baclofen induced a decrease in

blood flow in the medial orbitofrontal cortex, insula, and

ventral striatum, and an increase in blood flow in the cer-

ebellum and frontal cortex, including the lateral orbito-

frontal cortex [16]. The other study with a crossover design

acquired data using pseudo-CASL perfusion fMRI in 20

nicotine-dependent subjects [17] after a single dose of

20 mg baclofen, and in another session without medica-

tion. The subjects smoked freely before each session.

Baclofen induced decreases in cerebral blood flow in the

amygdala, dorsal anterior cingulate cortex, posterior cin-

gulate cortex, ventral anterior insula, and medial and lateral

orbitofrontal cortices. Increases in cerebral blood flow were

not observed [17].

3.2 Nicotine Replacement Therapy

We found 11 BOLD fMRI studies that examined the

effects of nicotine replacement therapy (NRT) on resting-

state or task-related cerebral activations [18–28]. The

neural areas affected by nicotinic pharmacological agents

in fMRI studies are summarized in Fig. 2. Ten studies used

nicotine patches, and one study used nicotine lozenges.

Two studies used reduced nicotine content (RNC) ciga-

rettes and nicotine gum, in addition to nicotine patches. In

seven studies, cognitive tests were applied during fMRI.

Two studies examined cerebral responses during exposure

to smoking cues and NRT. One study employed a reward-

conditioning paradigm, and one study examined the resting

state. The main features and results of these imaging

studies are listed in Table 2.

Seven studies used BOLD fMRI during cognitive tests

in smokers using NRT or a placebo. In one study, 12

smokers [28] were administered an N-back verbal working

memory (VWM) task during two fMRI sessions (nicotine

versus a placebo patch) with 3 weeks in between. The

findings suggested that nicotine withdrawal has strong

effects on the brain response to a demanding working

memory task. Differences were observed between the

pattern of brain responses during the nicotine condition and

the placebo condition. In the left medial frontal gyrus and

left and right anterior temporal lobe there was a significant

deactivation during the test, which was even greater during

the nicotine withdrawal [28]. These suggest that

withdrawal has effects on brain responses to a task that

requires short-term memory performance (working

memory).

Lawrence et al. [23] carried out a study with 15 smokers

who performed the rapid visual information-processing

(RVIP) task during fMRI in two sessions each with a

21 mg transdermal nicotine patch or a placebo. In addition,

they compared the nicotine-free performance and task-

induced brain activation in the smokers and 14 non-

smokers. In all groups, RVIP task performance was asso-

ciated with an increased BOLD signal in the frontal regions

and bilaterally in the parietal cortex, thalamus, caudate,

anterior insula, middle occipital/fusiform gyrus and cere-

bellar culmen. A decreased BOLD signal was found in the

left frontal regions, bilateral anterior and posterior cingu-

late, insula and left parahippocampal gyrus. Smokers using

the placebo showed less task-induced activation in the

parietal cortex and caudate than non-smokers. A nicotine

patch improved task performance; increased signals in the

parietal and occipital cortices, thalamus and caudate; and

decreased signals in the parahippocampal gyrus and insula

[23]. These results suggest that NRT improves attentional

processing.

In another study [20], 17 smokers underwent a test of

visuospatial attention, using the spatial attentional resource

allocation task, 3 h after using their last cigarette. The

participants received a 21 mg nicotine patch or a placebo in

two sessions held at different times (at least 2 days apart).

Seventeen non-smoking individuals also participated in

one BOLD fMRI session. Administration of the nicotine

patch was associated with reduced omission errors and an

improved reaction time, along with decreased activity in

the anterior and posterior cingulate, left angular gyrus, left

middle frontal gyrus and bilateral cuneus. In the absence of

NRT, the BOLD signals did not differ between smokers

and non-smokers [20].

In a study with a similar design, Hahn et al. [19] carried

out BOLD fMRI during tasks of simple stimulus detection,

selective attention and divided attention in 18 smokers after

single-blind application of a 21 mg nicotine patch or pla-

cebo, as compared with 18 non-smokers. The average

BOLD signal did not differ between smokers without the

patch and non-smokers. In all task conditions, the nicotine

patch reduced activation in the left middle and inferior

frontal gyrus, right pre- and post-central gyrus, middle and

inferior temporal gyrus, middle and inferior occipital

gyrus, fusiform gyrus, thalamus, and primary visual cortex;

and induced or enhanced existing deactivation in the

medial frontal gyrus, rostral anterior cingulate cortex, left

middle temporal gyrus and parahippocampal gyrus. The

drug reduced the reaction time in stimulus detection and a

selective attention task [19]. Thus, nicotine induced or

enhanced deactivation in brain regions that coincide with


Ta

ble

2M

ain

fin

din

gs

fro

ma

syst

emat

icre

vie

wo

nn

ico

tin

icp

har

mac

olo

gic

alfu

nct

ion

alm

agn

etic

reso

nan

ceim

agin

g(f

MR

I)st

ud

ies

insm

ok

ers;

the

sear

chw

ent

up

toM

ay2

01

2in

Pu

bm

ed,

Psy

cIN

FO

and

Web

of

Sci

ence

Ref

eren

ces

Chal

lenge

Mea

nag

ein

yea

rs,

(n)

Mai

nsa

mple

char

acte

rist

ics

Sm

okin

gst

atus

Stu

dy

type

and

met

hodolo

gy

Mai

nfi

ndin

gs

Cole

etal

.

[18]

Nic

oti

ne

pat

chvs

pla

cebo

30.3

±1.7

8,

(17)

-13

men

and

4w

om

en

-S

moker

sw

ithout

neu

rolo

gic

alor

oth

er

psy

chia

tric

dis

ord

ers

-U

seat

leas

t10

cigar

ette

sa

day

for

atle

ast

1yea

rw

ith

norm

aluse

wit

hin

30

min

of

wak

ing

-A

ver

age

use

15.7

±5.4

cigar

ette

s/day

-D

ura

tion

of

smokin

g11.2

±6.6

yea

rs

-F

TN

D5.6

±1.7

-D

ouble

-bli

nd,

cross

over

,co

ntr

oll

edtr

ial

-A

fter

8h

abst

inen

ce,

par

tici

pan

tsre

ceiv

ed

2dose

sof

4m

gnic

oti

ne

pat

chor

pla

cebo

-R

esti

ng

BO

LD

fMR

I

-M

MW

Sw

asuse

dto

mea

sure

wit

hdra

wal

sym

pto

ms

-Im

pro

vem

ents

inab

stin

ence

corr

elat

edposi

tivel

yw

ith

chan

ges

inco

nnec

tivit

yof

contr

ol

syst

emof

care

,both

inbra

inre

gio

ns

that

contr

ibute

todef

ault

net

work

such

asm

edia

lpre

fronta

lco

rtex

and

thal

amus,

and

in

regio

ns

involv

edw

ith

syst

emre

war

d,

such

as

orb

itofr

onta

lco

rtex

Hah

net

al.

[19]

Nic

oti

ne

pat

chvs

pla

cebo

30,

(36)

-9

mal

ean

d9

fem

ale

hea

lthy

smoker

sw

ithout

oth

erpsy

chia

tric

dis

ord

ers

-11

mal

ean

d7

fem

ale

nonsm

oker

s

-R

ecru

ited

by

med

iaad

s

and

refe

rral

s

-A

ver

age

use

21

±5

cigar

ette

s/day

-D

ura

tion

of

smokin

g12.9

±6.6

yea

rs

-S

ingle

bli

nd,

contr

oll

edst

udy

-A

fter

3h

of

use

,ci

gar

ette

smoker

sw

ere

test

edtw

ice

(sel

ecti

ve

atte

nti

on

and

div

ided

atte

nti

on),

one

tim

eusi

ng

a

21

mg

nic

oti

ne

pat

ch;

the

oth

erti

me

usi

ng

apla

cebo

-N

onsm

oker

sdid

the

pro

cedure

intw

o

sess

ions

wit

hout

med

icat

ion

-B

OL

DfM

RI

whil

eper

form

ing

ate

stof

sele

ctiv

eat

tenti

on

and

div

ided

and

det

ecti

on

of

stim

ulu

s

-N

icoti

ne

reduce

dre

acti

on

tim

ein

sele

ctiv

eat

tenti

on

and

stim

ulu

sdet

ecti

on

-N

icoti

ne

reduce

dac

tivat

ion

infr

onta

l,te

mpora

l,

thal

amus

and

regio

ns

corr

elat

edw

ith

vis

ion

and

incr

ease

ddea

ctiv

atio

nin

def

ault

net

work

Hah

net

al.

[20]

Nic

oti

ne

pat

chvs

pla

cebo

30,

(34)

-6

mal

ean

d11

fem

ale

smoker

s

-6

mal

ean

d11

fem

ale

nonsm

oker

s

-R

ecru

ited

by

med

iaad

s

and

refe

rral

s

-A

ver

age

use

21

±4.3

cigar

ette

s/day

-D

ura

tion

of

smokin

g15.9

±8.2

yea

rs

-S

ingle

bli

nd,

contr

oll

edst

udy

-3

haf

ter

the

last

cigar

ette

,sm

oker

sw

ere

test

edtw

ice,

usi

ng

(i)

a21

mg

nic

oti

ne

pat

chan

d(i

i)a

pla

cebo

-N

onsm

oker

sdid

the

pro

cedure

intw

o

sess

ions

wit

hout

med

icat

ion

-B

OL

DfM

RI

duri

ng

the

cours

eof

atte

nti

onal

reso

urc

eal

loca

tion

spat

ial

task

-N

icoti

ne

impro

ved

atte

nti

onal

per

form

ance

by

dow

nre

gula

ting

rest

ing

bra

infu

nct

ion

inre

sponse

to

task

-rel

ated

cues

-T

oget

her

wit

hse

lect

ivit

yof

effe

cts

for

NR

T,

this

sugges

tsnic

oti

ne-

induce

dpote

nti

atio

nof

aler

ting

pro

per

ties

of

exte

rnal

stim

uli

Hong

etal

.

[21]

Nic

oti

ne

pat

chvs

pla

cebo

35.7

±11.1

,(1

9)

-14

men

and

5w

om

en

-H

ealt

hy

smoker

sw

ithout

oth

erpsy

chia

tric

dis

ord

ers

-R

ecru

ited

by

med

iaad

s

-E

duca

tion

13

±1.8

yea

rs

-U

seat

leas

t10

cigar

ette

s/day

,D

SM

-IV

nic

oti

ne

dep

enden

cecr

iter

ia

-F

TN

D4.3

±2.4

-A

ge

atw

hic

hsm

okin

gw

asin

itia

ted:

16.9

±5.7

yea

rs

-U

se15.6

±10.9

pac

ks/

yea

r

-D

ouble

-bli

nd,

cross

over

,ra

ndom

ized

contr

oll

ed

-U

sed

nic

oti

ne

pat

ch21/3

5m

gor

a

pla

cebo

soon

afte

rquit

ting

smokin

g,

3h

bef

ore

the

pro

cedure

-B

OL

DfM

RI

wit

hout

stim

ulu

s,w

ith

anal

ysi

sof

area

sof

inte

rest

-T

he

sever

ity

of

nic

oti

ne

dep

enden

ceco

rrel

ated

wit

hth

e

acti

vit

yof

the

circ

uit

sin

terc

onnec

ting

the

dors

al

ante

rior

cingula

teco

rtex

and

the

stri

atum

-N

RT

impro

ved

the

connec

tivit

ypat

tern

sof

the

cingula

te–neo

cort

ical

circ

uit

s

Janes

etal

.

[22]

Nic

oti

ne

pat

ch

plu

s

nic

oti

ne

gum

43.2

±11.5

,(1

3)

-13

wom

en

-H

ealt

hy

smoker

sw

ithout

oth

erpsy

chia

tric

dis

ord

ers

-R

ecru

ited

from

acl

inic

al

tria

lof

smokin

g

cess

atio

n

-U

seat

leas

t10

cigar

ette

s/day

for

pre

vio

us

6m

onth

s,w

ith

min

imum

expir

edca

rbon

monoxid

esc

reen

ing[

10

ppm

,cr

iter

iafo

r

nic

oti

ne

dep

enden

ceac

cord

ing

toD

SM

-

IV

-F

TN

D6.2

±1.5

-H

AM

-D2.3

±2.8

-U

nco

ntr

oll

edst

udy

-U

seof

21

mg

nic

oti

ne

pat

chfo

r4

wee

ks,

2w

eeks

and

14

mg

per

7m

gfo

r

2w

eeks,

and

use

of

nic

oti

ne

gum

2m

gif

nec

essa

ry

-B

OL

DfM

RI

afte

rpre

trea

tmen

tan

d

51.5

±11.3

day

sof

trea

tmen

t,w

ith

photo

sof

stim

ulu

sco

rrel

ated

tosm

okin

g

and

neu

tral

stim

ulu

s

Aft

erap

pro

xim

atel

y2

month

sof

NR

T,

fMR

Ish

ow

ed

incr

ease

dsi

gnal

inte

nsi

tyduri

ng

exposu

reto

trig

ger

s,

com

par

edw

ith

neu

tral

pic

ture

s,in

fronta

l,an

teri

or

and

post

erio

rci

ngula

te,

tem

pora

l,par

ieta

l,occ

ipit

alan

d

insu

lar

cort

ex,

thal

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4]

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g


the so-called default network during the tests, in associa-

tion with improved performance of the attention task.

Another study [18] of resting-state BOLD fMRI exam-

ined 17 smokers following a 4 mg nicotine lozenge with a

double-blind, placebo-controlled, crossover design after

8 h of abstinence. Compared with placebo, nicotine

reduced total scores on the modified Minnesota withdrawal

symptom (MMWS) scale. Positive correlations between

symptom reductions in the MMWS and treatment-related

changes in activity were identified in the left orbitofrontal

cortex, left dorso-medial prefrontal cortex and left thala-

mus. Conversely, negative correlations between symptom

reductions in the MMWS and treatment-related changes in

activity were identified in the right posterior insula, right

posterior middle/inferior temporal gyri, left post-central

gyrus and right precentral gyrus/central sulcus. MMWS

difference scores negatively correlated with functional

connectivity changes in the left mid-cingulate and left

lateral orbitofrontal cortices. Positive correlations were

found between MMWS difference scores and functional

connectivity changes in the left dorsal hippocampus,

bilateral precuneus and bilateral parahippocampal gyri

[18]. Nicotine lozenge administration in abstinent smokers

modulated large-scale cognitive brain networks. The

improvement in clinical symptoms of smoking abstinence

after NRT, as assessed by the MMWS, positively corre-

lated with changes in the connectivity of the executive

control and default networks, highlighting functional inte-

gration and interaction between these circuits [18]. This

study thus provides additional evidence that acute NRT

modulates brain processes implicated in attention, memory

and executive control.

Twenty-five smokers [25] were scanned by BOLD fMRI

after a 21 mg nicotine patch or placebo, randomized and

counterbalanced, during performance of the intention/

attention task (IAT) twice. Twenty-three healthy controls

were studied for comparison. These 48 individuals were

given this choice reaction time (IAT) in which they man-

ually responded to a lateralized target light to the left or

right of a central fixation point. Before the onset of the

target stimulus, two midline warning stimuli were presented

that indicated where in the space the target stimulus would

occur (an attentional cue) and which hand the subjects

would have to use for responding (an intentional cue). The

NRT condition had no significant effects on the reaction

time, but smokers were more accurate overall than controls

across all task levels. In smokers with a nicotine patch

compared with those with a placebo, there were significant

increases in the BOLD signal in response to hand stimuli

(intentional) in the left inferior parietal lobule and in the

supramarginal, right superior temporal and left postcentral

gyri. After attentional stimuli, there was a significant

decrease of the signal in left postcentral gyrus. In smokersTa

ble

2co

nti

nu

ed

Ref

eren

ces

Chal

lenge

Mea

nag

ein

yea

rs,

(n)

Mai

nsa

mple

char

acte

rist

ics

Sm

okin

gst

atus

Stu

dy

type

and

met

hodolo

gy

Mai

nfi

ndin

gs

Suth

erla

nd

etal

.[2

7]

Nic

oti

ne

pat

chvs

pla

cebo

30,

(57)

-14

mal

ean

d16

fem

ale

hea

lthy

smoker

sw

ithout

oth

erpsy

chia

tric

dis

ord

ers

-9

mal

ean

d16

fem

ale

nonsm

oker

s

-R

ecru

ited

by

med

iaad

s

-S

mokin

gdet

erm

ined

by

Fag

erst

rom

test

-A

ver

age

use

22.4

±1.2

cigar

ette

s/day

-D

ura

tion

of

smokin

g15.7

±1.6

yea

rs

-S

ingle

-bli

nd,

contr

oll

edst

udy

-S

moker

ssm

oked

appro

xim

atel

y3

h

bef

ore

the

pro

cedure

and

use

d21

mg

nic

oti

ne

pat

chan

da

pla

cebo

intw

osc

ans

-N

onsm

oker

sdid

not

use

med

icat

ion

and

under

wen

tth

epro

cedure

-B

OL

DfM

RI

wit

hper

form

ance

of

centr

al

exec

uti

ve

funct

ionin

g-e

ven

t-re

late

dta

sk

-S

moker

san

dnonsm

oker

shad

acti

vat

ion

inpre

fronta

l

cort

exan

dm

edia

lsi

de,

ante

rior

insu

laan

dpar

ieta

l

regio

ns

-S

moker

shad

hig

her

tonic

acti

vat

ion

infr

onta

lco

rtex

above

aver

age

inri

ght

ante

rior

insu

laan

dan

teri

or

pre

fronta

lco

rtex

bil

ater

ally

,not

rela

ted

toab

stin

ence

or

nic

oti

ne

repla

cem

ent

Sw

eet

etal

.

[28]

Nic

oti

ne

pat

chvs

pla

cebo

38.6

±12.9

,(1

2)

-11

men

and

7w

om

en

-H

ealt

hy

smoker

sw

ithout

oth

erpsy

chia

tric

dis

ord

ers

-R

ecru

ited

thro

ugh

new

spap

erad

san

dfl

yer

s

-A

ver

age

use

13.4

2±

5.6

6ci

gar

ette

s/day

-F

TN

D2.1

7±

5.6

9

-C

ontr

oll

edst

udy

-U

seof

21

mg

nic

oti

ne

pat

chor

apla

cebo

ina

scan

3h

bef

ore

the

pro

cedure

-B

OL

DfM

RI

duri

ng

real

izat

ion

of

the

2-b

ack

ver

bal

work

ing

mem

ory

task

-D

isab

lere

late

dto

smokin

gab

stin

ence

was

gre

ater

in

left

mid

dle

fronta

lgyru

san

dri

ght

ante

rior

tem

pora

l

lobe

and

left

-N

odif

fere

nce

sin

acti

vat

ion

area

s

BO

LD

blo

od

oxygen

level

-dep

enden

t,E

EG

elec

troen

cephal

ogra

m,

DSM

-IV

Dia

gnost

ican

dS

tati

stic

alM

anual

of

Men

tal

Dis

ord

ers,

4th

Edit

ion,

FT

ND

Fag

erst

rom

test

for

nic

oti

ne

dep

enden

ce,

HA

M-D

Ham

ilto

ndep

ress

ion

scal

e,

MM

WS

modifi

edM

innes

ota

wit

hdra

wal

sym

pto

msc

ale,

NR

Tnic

oti

ne

repla

cem

ent

ther

apy


using the placebo compared with non-smokers, there were

higher signals in the left superior temporal and inferior

frontal gyri; in the right superior temporal gyrus for atten-

tional stimuli only; and in the left postcentral and right

anterior gyri when contrasting intentional with attentional

stimuli. Comparing controls with smokers in the NRT

condition, activation in the bilateral inferior frontal, middle

frontal and superior temporal gyri, anterior cingulate cortex,

insula and right postcentral gyrus was significantly greater

in smokers. Smokers with the nicotine patch showed

increased activity following intentional (versus attentional)

stimuli in the left inferior parietal lobule, postcentral gyrus,

superior and middle temporal gyri, and bilateral precuneus,

whereas controls showed the opposite effect. Smokers also

showed significant decreases in the response to attentional

stimuli in the bilateral occipital gyri and the left middle

temporal gyrus [25]. NRT improved accuracy but not the

reaction time, for both selective attention and motor inten-

tion, and significantly increased priming (i.e. an implicit

memory effect in which exposure to a stimulus influences

the response to a later stimulus) on the response to inten-

tional stimuli in brain regions known for mediating inten-

tion/response readiness (the inferior parietal lobe and

supramarginal gyrus) and motor preparation (the left post-

central gyrus) [25]. These results suggest that the behav-

ioural effects of NRT in smokers are not limited to selective

attention but are generalized to motor intention.

In another study [27], 30 smokers were scanned twice

with a nicotine or placebo patch, and were compared with

27 non-smokers during performance of the central execu-

tive functioning-event-related (CEFER) task. This study

used a mixed block/event-related design, which allowed

isolation of specific central executive operations (atten-

tional switch events) within general working memory

function (task blocks). In all participants, task block per-

formance enhanced activations in the medial superior

frontal cortex extending into the supplemental motor area,

the right and left lateral prefrontal cortex, and the bilateral

anterior insula/frontal operculum, putamen, parietal, and

cerebellar regions; and induced deactivations in the rostral–

medial prefrontal cortex, posterior cingulate cortex, and

bilateral parietal, temporal, and parahippocampal regions.

Attention switching induced activity in the supplemental

motor area/medial superior frontal cortex, left lateral pre-

frontal cortex, and left superior parietal and right superior

frontal regions; and induced deactivation in the rostral–

medial prefrontal cortex and posterior cingulate cortex.

NRT reduced craving. NRT-induced changes in brain

activation were not detected when the task blocks or switch

event effects were compared between the nicotine and

placebo conditions. In the task blocks, comparison between

smokers and non-smokers showed greater activation in the

medial superior frontal cortex, bilateral anterior prefrontal

cortex and right anterior insula/frontal operculum in

smokers [27].

Two BOLD fMRI studies scanned smokers who used

NRT or a placebo during exposure to smoking cues. In a

non-controlled trial [24], 16 dependent smokers were

scanned using BOLD fMRI at baseline, following

2–4 weeks of smoking RNC cigarettes while using a 21-mg

nicotine patch, and 2–4 weeks after quitting smoking. The

BOLD signal was less negative in response to smoking

cues than control cues in the ventral anterior cingulate

gyrus. In the amygdala, the responses to smoking cues had

significantly higher amplitudes than the responses to neu-

tral stimuli at the initial fMRI; however, these effects were

reversed during treatment. In the caudate, there was sig-

nificantly higher activation to smoking and neutral cues in

the pre-treatment scan than in the post-treatment scan. In

four participants who were abstinent (as opposed to those

who relapsed and smoked their usual cigarettes during

treatment), the responses to smoking cues had higher

amplitudes in the thalamus and ventral striatum than

responses to neutral stimuli at the initial examination,

which was reversed during treatment. In contrast, those

who relapsed showed no differences between responses to

cues at all scans [24]. The responses to visual smoking cues

were attenuated at the same rate with increased potentiation

of the response to neutral stimuli in the amygdala, thalamus

and ventral striatum. The results of this study suggest that

the treatment that was implemented modulated cue reac-

tivity in regions of the brain processing external stimuli.

Another study [22] used BOLD fMRI in 13 women

exposed to smoking-related and neutral images, before and

after extended smoking abstinence with NRT using patches

and gum. In the pre-treatment phase, the BOLD fMRI

response was increased during exposure to triggers com-

pared with neutral pictures, in the frontal, anterior, and

posterior cingulate cortices, the temporal, parietal and

occipital cortices and the cerebellum; and a reduced signal

was found in the middle occipital and inferior temporal

gyri. After approximately 2 months of NRT, fMRI showed

increased signal intensity during exposure to triggers,

compared with neutral pictures, in the frontal, anterior, and

posterior cingulate cortices, the temporal, parietal, occipital

and insular cortices, the thalamus, caudate nucleus and

claustrum; and reduced activation in the subcallosal,

parahippocampal, fusiform and inferior occipital gyri.

After comparison between periods, increased activity

related to long smoking abstinence was found in the

frontal, anterior cingulate, posterior cingulate, temporal

and parietal cortices, and in the caudate nucleus. A reduced

BOLD signal was found in the hippocampus [22]. There-

fore, there is evidence that extended smoking abstinence

reactivity to stimuli related to smoking persists in brain

areas involved in craving and conditioned cue responding,


which may contribute to persistent vulnerability to relapse,

even with NRT.

Given the evidence of the cingulate cortex being fre-

quently involved in tobacco dependence and nicotine

treatment [21], a study focused on this region of interest

specifically during resting-state fMRI. In a double-blind,

placebo-controlled, crossover design study, 19 smokers

smoked up to 3 h before the procedure and used a nicotine

patch of 21 mg or 35 mg, or a placebo. The severity of

nicotine dependence correlated with the activity of the

circuits interconnecting the dorsal anterior cingulate cortex

and the striatum, but administration of the nicotine patch

did not modulate this circuit activity. NRT improved the

connectivity patterns of the cingulate–neocortical circuits

[21]. These findings suggest that NRT can improve cog-

nitive functions but does not necessarily correct changes in

the brain circuitry associated with nicotine dependence.

In another study [26], 21 smokers and 21 non-smokers

were trained to associate a juice reward with a visual cue in

a classical conditioning paradigm and were scanned in two

identical fMRI sessions in which they were exposed to tri-

als. Smokers had a 21 mg nicotine patch or a placebo placed

before scanning. The analysis focused on mesocorticolim-

bic and nigrostriatal regions (dopamine pathways), which

support temporal difference error (TDE) processing, a

function that reports back the difference between the esti-

mated reward at any given state or time step and the actual

reward that is received. Across the fMRI sessions, the

subjects were exposed to trials where they either received

juice as temporally predicted or where the juice was with-

held (negative TDE) and later received it unexpectedly

(positive TDE). In analysis of the Tobacco Craving Ques-

tionnaire in the nicotine patch condition, the smokers were

more relaxed, content, focused, satisfied and less hungry;

following the placebo, the smokers experienced higher

smoking expectancy and purposefulness. NRT administra-

tion in smokers did not alter activity in any region of interest

compared with the placebo condition. There was a main

effect of the group (smokers versus non-smokers) in all

striatal subregions (i.e. the nucleus accumbens, caudate,

putamen) and in the medial prefrontal cortex, resulting from

comparatively reduced activation in smokers, but there was

no effect on activity in the midbrain. In the analysis of

smoking history, smoking-related reductions in activity in

these regions correlated with the duration in years of

smoking, and was therefore influenced by smoking chro-

nicity [26]. These findings suggest a differential effect of

chronic nicotine exposure on the neural substrates of reward

in distinct dopaminergic pathway regions and a failure of

NRT to alter these reward-related functional processes.

Again, it appears that acute NRT administration is insuffi-

cient to modify reward processing and the changes in the

brain circuitry associated with smoking.

4 Discussion

4.1 Non-nicotinic Pharmacological Treatment

4.1.1 Varenicline

Nicotine binds with high affinity to neuronal nicotinic

acetylcholine receptors (nAChRs-a4b2). In abstinent

smokers, the level of free a4b2 nAChRs is associated with

the desire to smoke [29]. Varenicline, a partial agonist of

a4b2 nAChRs with indirect action on the mesolimbic

dopamine system, is the newest drug for smoking cessa-

tion. Besides reducing the urge to smoke, it has been shown

to reduce withdrawal symptoms and to modify cognitive

and affective symptoms that lead to relapse [30]. People

who use the medication have significantly lower levels of

withdrawal symptoms, smoking urges and negative affect,

and significantly higher levels of positive affect, sustained

attention and working memory [30].

Considering the findings of the present review, the

reciprocal actions in the medial orbitofrontal cortex and in

the lateral orbitofrontal cortex seem to result in a decreased

response to stimuli related to smoking. Varenicline has

been shown to diminish cue-elicited responses in the ven-

tral striatum and medial orbitofrontal cortex [11]. In

addition, nicotine withdrawal appears to impair working

memory at high levels of difficulty, and varenicline may

increase memory-related brain activity in this brief period

of abstinence from nicotine, particularly in heavy smokers

[12].

The three double-blind studies found in this review [11–

13] examined the effects of varenicline in smokers in dif-

ferent situations: cue reactivity and craving, cognitive

impairment (working memory) and emotional processing.

The results suggest that varenicline has distinct actions on

these cognitive and affective processes that may contribute

to its clinical efficacy. The effects on diminished responses

in the BOLD signal to cue triggers in the ventral striatum

and medial orbitofrontal cortex contribute to decreased

craving. Decreased responses in the medial orbitofrontal

cortex, along with increased activity in the right lateral

orbitofrontal cortex, seem to result in decreased cue reac-

tivity. Varenicline may also increase brain activity related

to working memory during withdrawal in heavy smokers.

The observed effects of the drug on the BOLD signal did

not seem to correlate with affective changes that were not

related to smoking, but did correlate with emotional

responsiveness to smoking cues.

In a cue-reactivity scenario analyzed by fMRI, vareni-

cline was associated with a diminished response to smok-

ing cues in the medial orbitofrontal cortex and ventral

striatum [11]. The orbitofrontal cortex and the ventral

striatum are important brain substrates of smoking


cue-induced craving and had increased activity in these

situations of exposure to stimuli [31]. The ventral striatum

exerts control over emotional and motivational behaviour,

such as control over craving [32], and the medial orbito-

frontal cortex is involved in the representation of the

affective value of reinforcers and in decision making for

rewards [33]. Varenicline increased activity in the anterior

and posterior cingulate, inferior, middle and upper frontal

gyri, and in the lateral orbitofrontal and dorsolateral pre-

frontal cortices. Increased activity in the right lateral

orbitofrontal cortex correlated with a decrease of reactivity

of the medial orbitofrontal cortex [11]. The lateral regions

of the orbitofrontal cortex are more likely to be involved in

re-evaluating previously rewarded behaviour, when the

response selected requires suppression of previously

rewarded responses [34]. At rest, there was decreased

activity in the right amygdala, a region that mediates fast

responses to emotions [11].

Varenicline seems to result in a decreased response to

stimuli related to smoking; it reduces craving by dimin-

ishing responses to smoking cues in the medial orbito-

frontal cortex and ventral striatum while increasing activity

in the lateral orbitofrontal cortex. This distinctive dual

action may contribute to its clinical efficacy.

Abstinence from nicotine/tobacco produces a range of

withdrawal symptoms, including impaired verbal and

working memory, which may contribute to the difficulty

of smoking cessation [35, 36]. Working memory is a

cognitive process that enables information to be held and

managed. During working memory, varenicline increased

the BOLD signal in the dorsal anterior cingulate, medial

frontal and bilateral dorsolateral prefrontal cortices [12],

in association with faster performance in heavily depen-

dent smokers and increased brain activity related to

memory during withdrawal. The dorsolateral prefrontal

cortex plays an important role in short-term memory and

executive functions through direct anatomical connectiv-

ity with the dorsal cingulate cortex and medial thalamus

[37–39].

As discussed above, some of the efficacy of this drug

could be attributed to the regulation of emotion during

withdrawal, but there was no demonstration on fMRI of

affective changes related to smoking during varenicline

treatment [13]. We suggest that stress increases the

incentive salience of drug cues and, in this scenario, the

modulation in the prefrontal areas and in the limbic system

by varenicline reduces craving in stressful situations.

Moreover, there are varenicline effects on some brain areas

especially related to nicotine-craving [40] (the dorsolateral

prefrontal and orbitofrontal cortices). A recent study [40]

indicated that the dorsolateral prefrontal cortex builds up

value signals based on knowledge of nicotine availability,

and supports a model wherein aberrant circuitry linking the

dorsolateral prefrontal and orbitofrontal cortices may

underlie smoking addiction.

4.1.2 Bupropion

As an atypical antidepressant, bupropion has improved

rates of smoking cessation in patients with depression and

has became a common option for smoking cessation

worldwide [41]. Smokers treated with bupropion have

lower levels of irritability, less difficulty in concentrating,

and less craving and negative affect [42].

Changes in activation in the brain regions related to

reduction of the urge to smoke [15] suggest that modulation

of activities in the limbic regions and prefrontal cortex by

bupropion may directly decrease craving. There is a lack of

studies using fMRI in patients using bupropion plus NRT, a

treatment combination widely used in clinical practice.

In the smoking cue-reactivity fMRI study described in

the only study found in the present review, bupropion

reduced activation in the ventral striatum, medial orbito-

frontal cortex and anterior cingulate cortex bilaterally [15].

The anterior cingulate cortex is part of a circuit that serves

to regulate both cognitive and emotional processing [43].

This limbic region plays an important role in responding to

the emotional significance of stimuli and to performance

errors, and in preventing responses to inappropriate stim-

uli—processes that are implicated in emotion and attention

disorders [32]. The modulation by bupropion of limbic and

prefrontal cortical activity may decrease craving in a way

similar to the action of varenicline.

4.1.3 Baclofen

Baclofen, an agonist of B gamma-aminobutyric acid

receptor (GABA B) used in the treatment of spasticity, has

been studied for its effects on addictive behaviours.

Although not used as a first-line treatment, baclofen is used

in the treatment of alcohol dependence [44–48]. In a

9-week, double-blind, placebo-controlled pilot trial of

baclofen for smoking reduction, there was a reduction in

the number of cigarettes smoked per day [49].

Considering the two studies found in the present review

[16, 17], baclofen seems to modulate the activity of brain

regions involved in motivated behaviour and in reward

processing. These findings suggest its potential in amelio-

rating craving and reducing addictive behaviours. Studies

with baclofen to examine cue reactivity as well as cogni-

tive and emotional processing in smokers are necessary to

provide better insight into the mechanisms behind the

potential actions of baclofen in smoking cessation.

In resting baseline fMRI sessions, use of baclofen

decreased signals in the medial orbitofrontal cortex, insula,

ventral striatum, amygdala, dorsal anterior cingulate cortex


and posterior cingulate cortex [16, 17]. The amygdala inte-

grates a circuit that mediates the acquisition and expression

of conditioning by the limbic cortex, playing a key role in

drug-seeking behaviour and relapse into drug use [50]. The

insula, a region implicated in conscious urges, is gaining

considerable attention in addiction because smokers who

have acquired brain injuries—which include considerable

parts of the insular cortex—have stopped smoking sponta-

neously and immediately, and without persistence of the urge

to smoke, whereas addiction to cigarettes in smokers was not

interrupted when this region had minimal damage [51].

Another function of the insula relevant to addiction, corre-

lated with the ventral anterior portion, is to relay autonomic

sensations to the higher cortical processing structures, which

suggests a fundamental function of the insula in awareness

[52]. Maybe the posterior cingulate cortex can play a role in

addiction to cigarette smoking, as there is a case report of

immediate and complete cessation of smoking following a

lesion in this region [53]. Baclofen modulates regions

involved in reward and motivated behaviour, with a putative

efficacy mechanism based on neuroimaging findings in

reducing craving.

4.2 Nicotine Replacement Therapy

NRT reduces the motivation to smoke by replacing much

of the nicotine from cigarettes [54]. All of the commer-

cially available forms of NRT (gum, transdermal patches,

nasal sprays, inhalers and sublingual tablets/lozenges)

increase the rate of quitting by 50–70 % [55], regardless of

the setting, compared with control treatment (placebo).

Evidence shows that combining a nicotine patch with a

rapid delivery form is more effective than a single type of

replacement therapy [54].

In summary, the present review found some evidence

that NRT induced or enhanced the deactivation in the brain

regions that coincide with the so-called default network

during the tests [19, 20, 23, 28]. Only one study [27] found

differences between smokers and non-smokers in brain

activation related to working memory/control operations,

and NRT in smokers did not appear to augment neural

activity associated with executive control or general

working memory operations. There is some evidence that

during prolonged nicotine abstinence, reactivity to stimuli

that are related to smoking persists in brain areas involved

in craving and conditioned cue responding, which may

contribute to persistent vulnerability to relapse, even with

the use of NRT [22]. Finally, one study found that NRT

could improve cognitive function but not necessarily cor-

rect changes in the brain circuitry associated with nicotine

dependence [21].

NRT affects various cognitive processes, though most

studies in humans have focused on the amelioration of

cognitive deficits experienced during nicotine withdrawal

[56]. As already mentioned, the cognitive symptoms of

withdrawal such as inattention, poor concentration and

impaired memory contribute to relapse into smoking, and

NRT seems to improve this symptomatology [57].

During a verbal working memory task, deactivation

occurred in the left medial frontal gyrus and the left and

right anterior temporal lobe, and this was even greater

during nicotine withdrawal, suggesting that compensation

for inefficient neural processing can occur during craving

[28]. In one study, during a mixed block/event-related

fMRI, smokers showed greater activation in the medial

superior frontal cortex, bilateral anterior prefrontal cortex

and right anterior insula/frontal operculum throughout the

working memory task, compared with non-smokers [27].

These data suggest that smokers require greater recruitment

of working memory and supervisory control operations

during task performance. This fact could be a consequence

of an extended smoking history. In a sustained attention

task—a task that requires vigilance and working memory

for its execution—NRT improved performance and

induced increased signals in the parietal and occipital

cortices and in the thalamus and caudate, and decreased

signals in the parahippocampal gyrus and insula—areas

that were deactivated previously during the task [23]. The

task-induced BOLD activation provided by NRT in atten-

tion-related areas positively correlated with better perfor-

mance of these attentional resources on task demands,

which could reflect inhibition of somatosensory or emo-

tional processing.

In another attention task with stimuli of high and low

intensity, NRT improved performance and induced a

decrease in signals in the anterior and posterior cingu-

late, left angular gyrus, left middle frontal gyrus and

bilateral cuneus [19]. During tasks of simple stimulus

detection, selective attention and divided attention, NRT

improved performance in the first two tasks and reduced

activation in the left middle and inferior frontal gyrus,

right pre- and postcentral gyrus, middle and inferior

temporal gyrus, middle and inferior occipital gyrus,

fusiform gyrus, thalamus and primary visual cortex; and

induced or enhanced existing deactivation in the medial

frontal gyrus, rostral anterior cingulate cortex, left mid-

dle temporal gyrus and parahippocampal gyrus [19]. In

an intention/attention task, nicotine improved accuracy

and increased signals in response to intentional stimuli in

the left inferior parietal lobule, supramarginal gyrus,

right superior temporal gyrus and left postcentral gyrus;

after attentional stimuli, there was a significantly

decreased signal in the left postcentral gyrus [25]. In this

last study, NRT significantly increased the response to

intentional primes in brain regions that mediate response

readiness.


These fMRI studies show that withdrawal has effects on

the brain response to cognitive tasks. NRT seems to

modulate cognitive and behavioural brain networks largely

in smokers, including working memory, sustained atten-

tion, selective attention, motor intention and executive

control. These NRT actions ameliorate cognitive perfor-

mance, which improves smoking withdrawal symptoms.

The main factor for improvement seems to consist of

induced or enhanced deactivation in the brain regions of

the default network. The default network is characterized

by activation patterns during a ‘resting state’ of the brain—

while the subject is not focused on stimuli—and that are

disabled during focused activities [58]. A network of

resting-state brain function was first suggested by a meta-

analysis of PET studies, in which a consistent set of brain

regions displayed less activity during visual processing

tasks than in the absence of external task demands. In a

review [59], the areas that showed consistent decreases

during active tasks included the posterior cingulate/precu-

neus, some areas of the frontal cortex, the left inferior

temporal gyrus and the right amygdala. The task-induced

deactivation seems to represent reallocation of processing

resources from areas in which task-induced deactivation

occurs to areas involved in task performance [60]. In a

resting-state fMRI study, NRT improved cognitive with-

drawal symptoms with increased inversing coupling

between the executive control and default mode brain

networks [18], altering brain activity and functional con-

nectivity in ways that contribute to improvements in cog-

nition. These results suggest potentiation of warning of

external stimuli triggered by NRT, improving the induced

inattention caused by withdrawal. Therefore, NRT seems

to facilitate neuronal mechanisms that are responsible for

transitions from the default mode network to regions that

favour responsiveness to external demands.

In a cue-reactivity fMRI study with NRT during an

extended smoking abstinence period of 2 months, greater

activity was detected during extended abstinence than

during the pre-quit assessment in the prefrontal, primary

somatosensory, temporal, parietal, anterior cingulate and

posterior cingulate cortices, and in the caudate nucleus

[22]. This fact suggests that during extended smoking

abstinence, the reactivity to smoking cues versus neutral

stimuli persists and is increased in brain areas that have

been shown to correlate with increased reactivity to

smoking cues, and are involved in emotional processing,

visuospatial processing, attention and motor planning, and

that this may contribute to persisting relapse vulnerability.

A region-specific resting-state fMRI study analyzed the

cingulate cortex, and NRT improved connectivity patterns

of the cingulate-neocortical circuits, whereas the severity

of nicotine dependence correlated with circuits intercon-

necting the dorsal anterior cingulate cortex and the striatum

[21]. This contrast may be clinically relevant, explaining

the transient enhancement of behavioural and cognitive

functions in tasks and the unsatisfactory efficacy of NRT in

the long-term quit rate, suggesting that cingulate involve-

ment in nicotinic actions and dependence may not be

explained by simple local decreases or increases of activ-

ity. Another different study utilized a classical conditioning

paradigm and observed that NRT did not alter reward-

related functional processes [26]. All of these studies

suggest that NRT administration is insufficient to modify

reward processing and changes in the brain circuitry

associated with the chronic smoking. This fact could

explain the failure to maintain nicotine abstinence associ-

ated with difficulty in modulating negative affect.

There are a growing number of studies that have evaluated

the role of non-pharmacological factors such as taste and

environmental conditioning in the maintenance of smoking

and its relapse [61]. Considering this, a study evaluated the

BOLD fMRI effect of a nicotine patch and RNC cigarettes in

smoking cues for an extinction-based smoking cessation

treatment [24]. Use of sensory aspects of cigarette smoking

during treatment without the usual doses of nicotine, such as

RNC cigarettes, has been shown to produce satiety equiva-

lent to that achieved by regular cigarette smoking [62].

Treatment based on NRT associated with RNC cigarettes has

shown potential effectiveness in smoking cessation and

offers less concern about the toxic effects of excessive

consumption of nicotine in those smokers who do not quit

smoking during treatment [63]. The extinction-based treat-

ment in this BOLD fMRI study simultaneously attenuated

the cue reactivity in the amygdala while potentiating

responses to control cues; this pattern was also observed in

the thalamus of future abstinent smokers only (after 1 month

of continuous abstinence).

Despite divergent results regarding NRT effects found in

our review [19, 22], the thalamus has also been shown to be

active in response to drug cues. A recent study pointed out

that smokers have greater activity after exposure to smoking-

related images than after exposure to neutral images in

mesolimbic dopamine reward circuits that are known to be

activated by addictive drugs, including the thalamus [64].

Alcohol-dependent subjects have increased brain activity in

the thalamus when exposed to alcohol cues [65]. In another

study, thalamic metabolic activity was related to the arousal

modulating effects of nicotine [66]. These regulations in the

amygdala and thalamus after an extinction-based treatment

with RNC cigarettes and transdermal nicotine patches sug-

gest that this treatment can alter brain responses to smoking

cues too and that the changes may be associated with treat-

ment outcome. However, in view of the different findings of

the studies by Hahn et al. [19] and Janes et al. [22], we can

postulate that there is still a need for further clarification of

the effects of NRT on thalamus activity during exposure to


triggers, since both studies differed in terms of design. One

study tested acute NRT effects [19], and the other tested NRT

2-month effects [22].

4.3 Limitations

An important limitation of the present study is our exclu-

sion of smoking treatment PET studies. PET assessments

of regional cerebral blood flow, or the metabolic rate for

glucose, could offer an additional important imaging

modality to increase our understanding of brain function in

this field. However, we would have had to include other

terms in the database search (e.g. PET, PET-CT, PET

imaging and others), to include all relevant PET studies. A

minor limitation was the exclusion of sMRI studies (which

do not have an additional fMRI scan phase), as these

studies do not assess regional cerebral blood flow or any

metabolic rates, and would be difficult to compare with

fMRI studies.

The present review did not assess the risk of bias in

individual studies. This risk was also not assessed across

studies. No method of handling data and combining the

results of studies was carried out. Another limitation was

the inclusion of English language studies only.

5 Conclusions

Findings from the present review show that nicotinic and

non-nicotinic pharmacotherapies could facilitate smoking

cessation via different neural mechanisms. Varenicline and

bupropion seem to modulate cue-related activity in the

prefrontal and limbic areas including the anterior cingulate

cortex, ventral striatum and medial orbitofrontal cortex.

Baclofen also appears to have efficacy in the treatment of

smoking due to its modulation of the activity of brain

regions involved in motivated behaviour and in reward

processing. However, NRT seems to improve cognitive

symptoms related to withdrawal by modulating the activi-

ties of the default network. Notwithstanding that, from the

clinical literature, it is clear that NRT also alleviates neg-

ative affect symptoms of withdrawal [67]. Thus, our find-

ings may be biased, on the basis that the fMRI studies

primarily focused on cognitive effects.

Findings from these fMRI studies may aid the devel-

opment of new medications to treat nicotine dependence:

• Novel medications that modulate the prefrontal areas

and the limbic system seem promising. They could

reduce craving to smoke cigarettes in stressful situa-

tions, based on the findings of fMRI studies using

varenicline and bupropion—two medications that have

proven their clinical efficacy within smoking treatment.

Baclofen seems to modulate the activity of these brain

regions and is an interesting candidate for randomized

controlled trials of smoking treatment. Other well-

known non-nicotinic medications that modulate these

areas and that are potential candidates for fMRI pilot

studies testing the craving of smokers to smoke

cigarettes include topiramate, naltrexone, modafinil,

methylphenidate and atomoxetine. Topiramate seems to

raise limbic cortex (anterior cingulate) glutamine levels

in healthy men [68]. Naltrexone pharmacotherapy in

opioid-dependent patients may, respectively, decrease

and potentiate prefrontal and limbic cortical responses

to drug cues [69], and may thus also diminish craving

for tobacco. Modafinil seems to reduce BOLD signals

in the prefrontal cortex and anterior cingulate during

cognitive tasks in healthy volunteers [70], and may act

as a pharmacological agent to improve cognitive

functions in smoking withdrawal; however, there was

a recent trial of this medication in smokers, which

found no efficacy and poor tolerability [71]. Methyl-

phenidate seems to modulate dopaminergically inner-

vated prefrontal cortical areas involved in error-related

processing, among both healthy volunteers and

cocaine-dependent subjects [72] and it may therefore

also improve cognitive control over smoking behaviour

in smokers who want to quit. Atomoxetine has been

associated with increased fMRI activation of the

dorsolateral prefrontal cortex in adults with attention

deficit hyperactivity disorder [73], and in smokers it

may improve attentional bias within smoking

withdrawal.

• Despite several NRT options for the treatment of

nicotine dependence, novel non-nicotinic medications

that modulate activities of the default network could be

developed in order to ameliorate smoking withdrawal

symptoms. Other well-known medications that could be

used in fMRI pilot studies with smokers to test potential

improvement in cognitive symptoms related to nicotine

withdrawal include modafinil, methylphenidate and

atomoxetine [74, 75]. Modafinil seems to modulate

default network in healthy adults [74] and could be a

candidate to that end. During rewarded trials, both

methylphenidate and atomoxetine produced the oppo-

site effect to reward—that is, attenuating reward and

working memory networks and enhancing task-related

deactivations in regions consistent with the default

mode network [75].

Acknowledgments None.

Conflict of interest Drs. Menossi, Goudriaan, Perico, Nicastri,

Andrade, D’Elia, Li, and Castaldelli-Maia have no conflicts of interest

related to the content of this review.


Sources of funding None.

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