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Imaging resilience and recovery in alcohol dependence

Katrin Charlet1,2, Annika Rosenthal2, Falk W. Lohoff1, Andreas Heinz2 & Anne Beck2

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA1 and Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité—Universitätsmedizin, Berlin, Germany2

ABSTRACT

Background and aims Resilience and recovery are of increasing importance in the field of alcohol dependence (AD). This paper describes how imaging studies in man can be used to assess the neurobiological correlates of resilience and, if longitudinal, of disease trajectories, progression rates and markers for recovery to inform treatment and prevention op- tions. Methods Original papers on recovery and resilience in alcohol addiction and its neurobiological correlates were identified from PubMed and have been analyzed and condensed within a systematic literature review. Results Findings deriving from functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies have iden- tified links between increased resilience and less task-elicited neural activation within the basal ganglia, and benefits of heightened neural pre-frontal cortex (PFC) engagement regarding resilience in a broader sense; namely, resilience against relapse in early abstinence of AD. Furthermore, findings consistently propose at least partial recovery of brain glucose me- tabolism and executive and general cognitive functioning, as well as structural plasticity effects throughout the brain of alcohol-dependent patients during the course of short-, medium- and long-term abstinence, even when patients only lowered their alcohol consumption to a moderate level. Additionally, specific factors were found that appear to influence these observed brain recovery processes in AD, e.g. genotype-dependent neuronal (re)growth, gender-specific neural re- covery effects, critical interfering effects of psychiatric comorbidities, additional smoking or marijuana influences or ado- lescent alcohol abuse. Conclusions Neuroimaging research has uncovered neurobiological markers that appear to be linked to resilience and improved recovery capacities that are furthermore influenced by various factors such as gender or genetics. Consequently, future system-oriented approaches may help to establish a broad neuroscience-based research framework for alcohol dependence.

Keywords Alcohol dependence, functional, neuroimaging, recovery, resilience, structural.

Correspondence to: Katrin Charlet, Section on Clinical Genomics and Experimental Therapeutics (CGET), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 10 Center Drive (10CRC/2-2340), Bethesda, MD 20892-1540, USA. E-mail: [email protected] Submitted 10 September 2015; initial review completed 26 January 2016; final version accepted 25 April 2018

INTRODUCTION

Imaging recovery and resilience

The toxic effects of alcohol are seen particularly in the brain, as demonstrated by several post-mortem and in-vivo neuroimaging studies in individuals with alcohol depen- dence (AD; e.g. [1–3]). Structural changes are observed clearly in the brain, including atrophy of gray and white matter with sulcal widening and ventricular enlargement. In addition, chronic alcohol consumption is accompanied by neural adaptations within different neurotransmitter systems, such as the dopamine system (cf. reviews [4–9]). These neural andmolecular changes have been shown fur- ther to be associated with dysfunctional brain functions underlying psychological and behavioral processes in AD [10–19].

Once harmful alcohol use stops or is reduced, beneficial recovery processes can be observed regarding physical and mental health (see [20]) and in the brain, using various neuroimaging techniques [21–24]. One of the main ques- tions for neuroimaging research in the field of addictive dis- orders is to characterize predictors of recovery and treatment outcome [25]. It is notable, however, that a clear standard definition of the term ‘recovery’ is not yet gener- ally established. In this review, we will focus on structural and functional changes within the brain associated with reduction of alcohol intake or abstinence in AD investi- gated by studies using neuroimaging techniques as identi- fied by our literature search.

Another consideration is to what extent abnormalities in brain structure and function are caused by the toxic ef- fects of alcohol, or whether some of these differences might

HORIZONS REVIEW doi:10.1111/add.14259

http://orcid.org/0000-0001-5405-9065

have been pre-existing and putatively predispose some indi- viduals to develop alcohol dependencewhile others seem to have a protective effect, i.e. confer resilience [26]. Resil- ience is defined traditionally as the ability to adapt to adverse/traumatic environments, thus resulting in healthy long-term psychological functioning and better develop- mental outcomes [27–29]. Resilience research also con- centrates on high-risk groups, which do not develop the disorder of interest despite carrying risk genes and/or experiencing adverse environmental conditions. Studying those individuals already affected, however, adds a new perspective to the understanding of disease development, disease progression and future potential treatment strate- gies by focusing on neurobiological factors that promote a good treatment outcome despite adversities. Thus, studies using neuroimaging techniques may help to identify such resilience mechanisms regarding the structural and func- tional markers of neural patterns associated with attenuat- ing further disease progression and/or relapse in AD [10,11,30,31]. Such factors are not defined by the absence of vulnerability markers, but rather by compensatory changes in biological markers that distinguish individuals with good treatment outcome from those who relapse and healthy controls.

We therefore reviewed the available literature to an- swer the following questions: (1) why are some people less vulnerable in developing addictive disorders in comparison with others; (2) to what extent can recovery processes be observed; and (3) why do some individuals with alcohol de- pendence achieve and maintain abstinence better, i.e. are more resilient than those who relapse?

METHODS

Search strategy

We reviewed systematically the existing literature up to November 2017 using the PUBMED electronic database for the identification of neuroimaging studies investigating recovery and/or resilience in alcohol dependence or alco- hol dependence in humans, respectively. We therefore used the following search terms: imaging, neuroimaging, addic- tion, dependence, alcohol*, substance use*, substance use disorder, recovery, resilience. Bibliographies of relevant pa- pers were additionally screened for further relevant information.

Study selection

We included peer-reviewed original studies irrespective of when the study was conducted and excluded single case studies, reviews and meta-analyses. For the sake of parsi- mony, we further excluded neuroimaging studies using im- aging techniques other than functional magnetic resonance imaging (fMRI), structural MRI, diffusion tensor

imaging (DTI) or positron emission tomography (PET). Ad- ditional exclusion criteria were: not in English, substances other than alcohol, neuropsychological studies without neuroimaging.

Extraction and quality assessment

One reviewer (K.C.) screened abstracts of papers identified for potential relevance. Then, two reviewers (A.B. and K.C.) extracted study data independently and screened further the bibliographies of relevant papers. In the event of uncertainty or disagreement regarding criteria for eligibility between A.B. and K.C., selected papers and manuscript drafts were discussed further with the third and fourth reviewers (F.W.L. and A.H.). Decisions on study selection were documented by A.R.

RESULTS

Search results

The initial term search identified a total of 1066 papers, 175 of which were considered potentially relevant. Addi- tionally, seven were identified through screening the refer- ence lists of selected papers. Of those, 145 papers were excluded further, as described in Fig. 1, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group [32]. Finally, 35 studies were included in our review (for details, please see Table 1 and Supporting information, Appendix S1).

Resilience and recovery markers detected by fMRI

We found nine relevant fMRI studies [10–12,33–38] inves- tigating the role of cognitive functions seen commonly in AD, such as executive, motivational aspects of behavior and emotion processing (for reviews, see [4,7,39]).

Weiland et al. characterized resiliency as the ability for flexible adaptation of psychological control functions ap- propriate to the respective environmental context [36]. As low resiliency is known to be associated with later alcohol/drug problems and poor working memory perfor- mance [36], they investigated young healthy adolescents with and without a positive family history for alcohol de- pendence using a 2-back working memory task and ob- servers’ ratings based on the California Child Q-Sort as a measurement for resiliency. Resiliency correlated nega- tively with number of alcohol problems and illicit drugs used but did not differ regarding family history. This might point to the importance of environmental factors apart from genetic influences.

Another study reported that in those with AD who be- came abstinent, higher functional engagement of brain areas within and outside of the ‘classical’working memory network (e.g. rostral/ventrolateral pre-frontal cortex) was

1934 Katrin Charlet et al.

associated with executive behavioral control [11]. This may constitute a resilience factor in terms of flexible re- cruitment of neural resources inside the classical working memory network and further compensatory processes as- sociated with longer duration of abstinence. This is consis- tent with another fMRI study that also showed functional recruitment of neural working memory network in alcohol dependence [33], and suggests that such higher activity is productive rather than an impairment.

Drug-associated cue–reactivity has been associated with drug craving (e.g. [16,40]) and risk of relapse after de- toxification (e.g. [10,14]). Two recent prospective studies reported altered cingulate cortex connectivity during indi- vidualized imaginary scripts provoking either alcohol-, stress-associated or neutral states in AD [38]. Those pa- tients who showed greater posterior cingulate connectivity during alcohol imagery, or less anterior, mid-cingulate con- nectivity during neutral trials, showed longer abstinence during the following 90 days and resembled healthy con- trols. These results emphasize the benefit of functional con- nectivity analyses in the investigation of neurobiological substrates and relapse risk in AD [38].

In their prospective study, Beck et al. [10] observed in- creased neural reactivity during presentation of alcohol- associated cues within mid-brain/subthalamic nucleus as well as ventral striatum in those AD who achieved absti- nence compared to relapsers (< 3 months’ follow-up) [10]. Further, patients who remained abstinent demon- strated increased functional connectivity between mid-

brain and amygdala as well as orbitofrontal cortex (OFC) during this alcohol-associated ‘cue–reactivity’ task com- pared to those patients who relapsed within 3 months. The authors argued that the increased connectivity be- tween dopaminergic brain areas such as the mid-brain and the amygdala/OFC might help to discriminate and sig- nal aversive aspects of drinking alcohol, and thus may sup- port abstinence.

In the context of reward deficiency, Yau et al. observed reduced ventral striatal response during the anticipation of monetary reward and loss using a monetary incentive delay task (MID) in a group of healthy children of alcohol-dependent (COA) individuals (aged 18–22 years) compared with controls [37]. In addition, in COAs only, ac- tivation of ventral striatum was correlated positively with externalizing behavior as well as current and life-time alco- hol consumption.

Another important but rarely studied domain in addic- tion research regarding recovery or resilience is the neural basis of emotion processing. Heitzeg et al. [35] conducted a longitudinal cohort study to investigate externalizing be- havioral problems and neural activation patterns during an fMRI task presenting emotional words in adolescents (aged 16–20 years) with a family history of AD who were considered vulnerable (risky drinking behavior) or resilient (no risky drinking behavior). These groups were compared to adolescents without any parental history of AD or risky drinking behavior [35]. In response to emotional stimuli, increased activation in OFC, insula and putamen was

Figure 1 Flow diagram of the selection process of studies for the systematic review on imaging resilience and recovery in alcohol dependence, ac- cording to Moher et al. (2009) [32] sMRI = structural magnetic resonance imaging; fMRI = functional magnetic resonance imaging; DTI = diffusion tensor imaging; PET = positron emission tomograph

1935

Ta bl e 1

Su m m ar y of ch ar ac te ri st ic s of 35

ne ur oi m ag in g st ud

ie s in cl ud

ed fo r in ve st ig at io n of re si lie nc e an

d re co ve ry

in al co ho

ld ep en de nc e.

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

A lh as so on

et al .2

01 2

Pr os pe ct iv e

co ho

rt st ud

y M R I/ D TI

N on

e N on

e 1 ye ar

A D :m

ea n 51

.4 SD

(6 )

Co nt ro ls :m

ea n 51

.8 SD

(7 .4 )

n m al e = 30

(d et ox ifi ed

al co ho

l- de pe nd

en t ↔

he al th y

co nt ro ls )

Lo w

FA an

d hi gh

R D in

co rp us

ca llo su m

of A D

gr ou

p co m pa re d to

co nt ro ls .S ig ni fi ca nt

im pr ov em

en t at

fo llo w -u p in

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A lv an

zo et al .2

01 5

Cr os s- se ct io na

l M R I/ PE

T N on

e Fa m ily

tr ee

qu es tio

nn ai re

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e FH

P: m ea n 23

.1 SD

(2 .9 8)

FH N :

m ea n 22

.7 SD

(3 .2 1)

n m al e = 51

, n fe m al e = 33

(fa m ily

hi st or y of

A D ↔

no fa m ily

hi st or y of A D )

Ba se lin

e [1 1C

]r ac lo pr id e BP

N D w as

ge ne ra lly

hi gh

er in

FH P co m pa re d w ith

FH N su bj ec ts

ac ro ss st ri at al re gi on

s. N eg at iv e su bj ec tiv e dr ug

ef fe ct s w er e m or e pr on

ou nc ed

in FH

P th an

in FH

N su bj ec ts .I n FH

N co rr el at io n be tw

ee n BP

N D an

d po si tiv e dr ug

ef fe ct s. Th

is co rr el at io n w as

le ss pr on

ou nc ed

in FH

P Be ck

et al .

20 12

Pr os pe ct iv e

co ho

rt st ud

y fM

R I/ bi ol og ic al

pa ra m et ri c

m ap pi ng

/P PI

A lc oh

ol cu es

N on

e 3 m on

th s

A D :m

ea n 39

.3 7

SD (7 .7 2)

co nt ro ls :m

ea n 40

.3 7

SD (6 .6 8)

n = 92

(d et ox ifi ed

A D ↔

he al th y

co nt ro ls )

A bs tin

en ce

re la te d to

in cr ea se d ac tiv

at io n in

m id -b ra in

an d V S. St ro ng

er fu nc tio

na l

co nn

ec tiv

ity m id -b ra in –l ef t am

yg da la an

d m id -b ra in –l ef t or bi to fr on

ta lc or te x. R el ap se

as so ci at ed

w ith

at ro ph

y in

bi la te ra l

or bi to fr on

ta lc or te x, ri gh

t m ed ia lP

FC an

d A CC

as w el la s in cr ea se d ac tiv

ity in

le ft m ed ia l

PF C

Bu rt et al .

20 16

Cr os s- se ct io na

l M R I/ V BM

N on

e ES PA

D ,S D Q ,

DA W BA

,L EQ

N on

e M ea n 14

.5 6

SD (0 .4 4)

n m al e = 90

6, n fe m al e = 96

4 [c om

pe te nt

(C /a ),

re si lie nt

(C /A

), m al ad ap tiv e (c /A

), vu

ln er ab le (c /a )]

C/ a an

d C/ A sh ow

ed la rg er

le ft O FC

vo lu m e

C/ a an

d c/ A la rg er

fu si fo rm

gy ru s vo lu m e th an

c/ a an

d C/ A gr ou

ps C/ A gr ou

p sh ow

ed in cr ea se d vo lu m e re la tiv e to

ot he r gr ou

ps in

ri gh

t su pe ri or

fr on

ta la nd

ri gh

t m id dl e fr on

ta l

re gi on

s; in

th e ri gh

t su pe ri or

fr on

ta lr eg io n

Ca rd en as

et al .2

00 7

Cr os s- se ct io na

l/ pr os pe ct iv e

co ho

rt st ud

M R I/ D BM

N on

e LD

H 8 m on

th s

(A D )

A D :m

ea n 49

SD (1 4)

Co nt ro ls :m

ea n

45 SD

(8 )

n m al e = 60

, n fe m al e = 5

(A D ↔

LD ;A

D lo ng

itu di na

A tr op hy

in fr on

ta la nd

te m po ra ll ob e in

A D

gr ou

p. A bs ta in er s sh ow

fa st er

re co ve ry

in pa ri et al an

d fr on

ta lt is su e th an

LD .

Te m po ra ll ob es ,t ha

la m us ,b ra in st em

(C on

ti nu

es )

1936 Katrin Charlet et al.

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

m on

th s

(L D )

↔ LD

) ce re be llu

m ,c or pu

s ca llo su m ,a nt er io r ci ng

ul at e,

in su la an

d su bc or tic al w hi te

m at te r w as

in cr ea se d in

ab st ai ne rs

co m pa re d to

re la ps er s.

R ec ov er y pr ed ic te d by

ba se lin

e gr ay

m at te r

vo lu m es

Ca rd en as

et al .2

01 1

Pr os pe ct iv e

co ho

rt st ud

y M R I/ D BM

N on

e LD

H 7. 8 m on

th s

A D :m

ea n 50

SD (1 0)

Co nt ro ls :

m ea n 47

SD (8 )

n m al e = 10

4, n fe m al e = 11

(A D <

he al th y

co nt ro l; re la ps er s

↔ ab st ai ne rs )

A bs ta in er s ve rs us

co nt ro ls ha

d sm

al le r vo lu m e

in le ft hi pp oc am

pu s, en to rh in al co rt ex ,a m yg da la

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us bu

t la rg er

vo lu m e in

le ft

or bi to fr on

ta lr eg io n.

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ab st ai ne rs

sm al le r vo lu m e in

la te ra lO

FC ,l ef t po st er io r

m id dl e/ te m po ra lg yr y an

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ar gi na

lg yr us .

R el ap se rs ha

d di ffe re nt

pa tt er n

of vo lu m e lo ss th an

ab st ai ne rs

Ch an

ra ud

et al .2

01 3

Cr os s- se ct io na

l fM

R I/ PP

I/ re st in g

st at e fu nc tio

na l

co nn

ec tiv

ity

W or ki ng

- m em

or y ta sk

N on

e N on

e A D :m

ea n 40

.1 SD

(1 0. 9)

Co nt ro ls :m

ea n 47

.7 SD

(1 2. 29

)

n m al e = 30

(d et ox ifi ed

A D ↔

he al th y co nt ro ls )

R ec ov er y re la te d to

re cr ui tm

en t of do rs ol at er al

pr e- fr on

ta lc or te x (D LP

FC )- ce re be lla r V II I sy st em

du ri ng

re st an

d D LP

FC -c er eb el la r V I sy st em

du ri ng

w or ki ng

m em

or y ta sk

Ch ar le t et al .

20 14

Pr os pe ct iv e

co ho

rt st ud

y fM

R I/ bi ol og ic al

pa ra m et ri c

m ap pi ng

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ol tim

e- lin

e fo llo w -b ac k

7 m on

th s

A D :m

ea n 44

.9 SD

(1 1. 4)

Co nt ro ls :m

ea n 44

.1 SD

(1 2)

n m al e = 60

, n fe m al e = 20

(d et ox ifi ed

A D ↔

H ea lth

y co nt ro ls )

H ig h re si lie nc e (lo

w re la ps e ri sk

in al co ho

l-d ep en de nc e)

as so ci at ed

w ith

ne ur al

ac tiv

at io n in

la te ra l/ m ed ia lp re -m

ot or

co rt ex ,

ro st ra l/ ve nt ro la te ra lp re -fr on

ta lc or te x du

ri ng

N -b ac k w or ki ng

m em

or y ta sk

Ch ar le t et al .

20 14

Pr os pe ct iv e

co ho

rt st ud

y fM

R I/ bi ol og ic al

pa ra m et ri c

m ap pi ng

H ar ir if ac es

ta sk

(m od ifi ed )

LD H

N on

e A D :m

ea n 44

.8 SD

(9 .8 )

Co nt ro ls :m

ea n 46

.1 SD

(9 .8 )

n m al e = 50

, n fe m al e = 16

(d et ox ifi ed

A D ↔

he al th y co nt ro ls )

In cr ea se d A CC

re sp on

se to

af fe ct iv e fa ce s

co rr el at ed

to ab st in en ce

an d le ss re tr os pe ct iv e

al co ho

li nt ak e in

al co ho

l-d ep en de nt

pa tie nt s

Ch un

g et al .

20 11

Cr os s- se ct io na

l Ev en t- re la te d fM

R I

A nt i-s ac ca de

re w ar d ta sk

N on

e N on

e SU

D :m

ea n 17

.0 SD

(0 .9 )

Co nt ro l: m ea n 16

.9 SD

(0 .9 )

n m al e/ fe m al e = 12

[S U D (m

ar iju

an a,

al co ho

l, ot he r)

↔ he al th y co nt ro ls ]

D ur in g re sp on

se pr ep ar at io n SU

D sh ow

ed in cr ea se d ac tiv

at io n in

oc ul om

ot or

co nt ro l

re gi on

s (F EF ,S EF ),

D LP

FC ,r eg io ns

in th e

pa ri et al lo be

an d ar ea s in

th e fr on

ta lg yr us (C on

ti nu

es )

1937

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

D es hm

uk h

et al .2

00 5

Cr os s- se ct io na

l M R I/ vo lu m et ri c

da ta

N on

e N on

e A D :m

ea n 49

.4 SD

(1 0. 9)

Co nt ro ls :m

ea n

45 .2 SD

(1 3. 9)

Sc hi zo ph

re ni a: m ea n

44 .7

SD (8 .6 )

Co m or bi d:

m ea n 41

.0 SD

(7 .5 )

n m al e = 12

2 (A D de to xi fi ed

↔ sc hi zo ph

re ni a

↔ A D /s ch iz op hr en ia

↔ he al th y co nt ro ls )

Pu ta m en

an d nu

cl eu s ac cu m be ns

de cr ea se

gr ea te r in

sc hi zo ph

re ni a th an

A D ,c om

or bi d

gr ou

p fe ll be tw

ee n th es e gr ou

ps Sc hi zo ph

re ni c

pa tie nt s tr ea te d w ith

at yp ic al m ed ic at io n

sh ow

ed gr ea te r vo lu m e de cr ea se s in

pu ta m en

th an

th os e tr ea te d w ith

ty pi ca lm

ed ic at io n.

R ec en tly

so be r (<

3 w ee ks ) al co ho

lic s ha

d gr ea te r de fi ci ts in

nu cl eu s ac cu m be ns

th an

A D w ith

lo ng

-t er m

so br ie ty

D ur az zo

et al .2

01 5

Pr os pe ct iv e

co ho

rt st ud

y M R I/ vo lu m et ri c

da ta

N on

e LD

H ,N

eu ro co gn

iti ve

ba tt er y

7. 5 m on

th s

A D sm

ok in g: m ea n

49 SD (9 )

A D no

n- sm

ok in g:

m ea n 52

SD (1 1)

Co nt ro ls :

M ea n 47

SD (9 )

n m al e = 10

3, n fe m al e = 11

A D :v ol um

e in cr ea se s in

al lG

M an

d W M

re gi on

s at

FU ;n

o si gn

ifi ca nt

pr ed ic to rs of

re gi on

al vo lu m e ch an

ge .R

at es

of G M

ga in

gr ea te st in

fi rs t m on

th .s A D sh ow

ed le ss

vo lu m e ga in

ns A D in

fr on

ta la nd

to ta l

co rt ic al G M .I m pr ov em

en t pr oc es si ng

sp ee d

as so ci at ed

w ith

in cr ea se d vo lu m es

in ns A D ,

bu t no

t in

sA D .A

fte r 7. 5 m on

th s of ab st in en ce ,

ns A D an

d sA

D eq ua

lt o co nt ro ls on

fr on

ta lG

M vo lu m e

G az dz in sk i

et al .2

00 5

Cr os s- se ct io na

l/ pr os pe ct iv e

co ho

rt st ud

M R I/ bo un

da ry

sh ift

in te gr al

N on

e LD

H U p to

12 m on

th s

A D :m

ea n 50

.6 SD

(9 .3 )

Co nt ro ls :m

ea n 45

.0 SD

(6 .8 )

n m al e = 37

, n fe m al e = 3

(A D de to xi fi ed /

lo ng

itu di na

l↔ he al th y co nt ro ls )

M os t tis su e ga in

du ri ng

th e fi rs t ab st in en t

m on

th .F as te st vo lu m e re co ve ry

pa tie nt s w ith

gr ea te st ba se lin

e br ai n sh ri nk

ag e an

d dr in ki ng

se ve ri ty .R

ev er sa lo fv ol um

e in cr ea se s in

no n- ab st in en t in di vi du

al s (m

od ul at ed

by du

ra tio

n of ab st in en ce

an d no

n- ab st in en ce

pe ri od s, as

w el la s re ce nc y

of no

n- ab st in en ce )

G az dz in sk i

et al .2

00 8

Cr os s- se ct io na

l/ pr os pe ct iv e

co ho

rt st ud

M R I/ sh or t ec ho

pr ot on

sp ec tr os co py

N on

e BV

M T

1 m on

th Sm

ok in g al co ho

l- de pe nd

en t: m ea n

50 .7

SD (9 .0 )

n m al e = 38

(s m ok in g A D ↔

no n- sm

ok in g

N -a ce ty l-a

sp ar ta te

no rm

al iz ed

in th e M TL

of no

n- sm

ok in g A D gr ou

p, re m ai ne d lo w

in th e

M TL

of sm

ok in g A D gr ou

p. Ch

an ge s in

bo th

(C on

ti nu

es )

1938 Katrin Charlet et al.

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

N on

-s m ok in g

al co ho

l-d ep en de nt :

M ea n 50

.2 SD

(9 .1 )

N on

- sm

ok in g co nt ro ls :

m ea n 47

.3 SD

(8 .2 )

A D ↔

no n- sm

ok in g LD

) gr ou

ps as so ci at ed

w ith

im pr ov em

en ts in

vi su os pa tia

lm em

or y.

H ip po ca m pa lv ol um

es in cr ea se d in

bo th

gr ou

ps du

ri ng

ab st in en ce ,b ut

in cr ea si ng

vo lu m es

co rr el at ed

w ith

vi su os pa tia

lm em

or y

im pr ov em

en ts on

ly in

no n- sm

ok in g A D

G az dz in sk i

et al .2

01 0

Pr os pe ct iv e

co ho

rt st ud

y M R I/ D TI /

sp ec tr os co py

N on

e N on

e 1 ye ar

Sm ok in g al co ho

l- de pe nd

en t: m ea n

47 .7

SD (9 .5 )

N on

-s m ok in g

al co ho

l-d ep en de nt :

m ea n 51

.5 SD

(1 0. 3)

N on

-s m ok in g

co nt ro ls :m

ea n 48

.3 SD

(8 .4 )

n m al e = 53

, n fe m al e = 5

(s m ok in g A D ↔

no n-

sm ok in g A D

↔ no

n- sm

ok in g LD

)

H ig he r m ea n di ffu

si vi ty

in A D (s m ok in g: fr on

ta l;

no n- sm

ok in g: pa ri et al ,f ro nt al ,t em

po ra l).

Lo w er

co nc en tr at io ns

of N -a ce ty l-a

sp ar ta te

in A D

(s m ok in g: fr on

ta l; no

n- sm

ok in g: pa ri et al ). In

no n-

sm ok in g al co ho

l-d ep en de nt

in di vi du

al s

in cr ea se

in FA

an d de cr ea se s in

m ea n di ffu

si vi ty

ov er

1 m on

th of ab st in en ce .W

hi te

m at te r

vo lu m e in cr ea se

in fr on

ta la nd

te m po ra ll ob es

in sm

ok in g A D gr ou

p H ei nz

et al .

20 04

Cr os s- se ct io na

l fM

R I/ PE

T A lc oh

ol cu es

A lc oh

ol cr av in g

qu es tio

nn ai re

N on

e A D :m

ea n 44

.5 SD

(6 .5 )

Co nt ro ls :

m ea n 43

.2 SD

(9 .5 )

n m al e = 24

(d et ox ifi ed

A D ↔

he al th y

co nt ro ls )

In al co ho

l-d ep en de nt

su bj ec ts hi gh

er ac tiv

at io n

of th e m ed ia lp re -fr on

ta lc or te x an

d st ri at um

re la te d to

(1 ) le ss av ai la bi lit y of D 2- lik e re ce pt or s

in V S, (2 ) hi gh

er cr av in g se ve ri ty

H ei tz eg

et al .

20 08

Cr os s- se ct io na

l fM

R I

Le xi ca l

em ot io na

l st im

ul i

Y SR

, D ri nk

in g an

d dr ug

hi st or y fo rm

fo r

ch ild re n

N on

e CO

A s

re si lie nt :m

ea n 18

.4 SD

(1 ) CO

A s

vu ln er ab le

:m ea n 17

.5 SD

(1 .3 )

Co nt ro ls :m

ea n 17

.2 SD

(1 .6 )

n m al e = 15

, n fe m al e = 13

(C O A s re si lie nt

↔ CO

A S vu

ln er ab le

↔ co nt ro ls )

In re sp on

se to

em ot io na

ls tim

ul i: ac tiv

at io n of

or bi ta lf ro nt al gy ru s an

d le ft in su la /p ut am

en gr ea te r in

re si lie nt

th an

co nt ro la nd

vu ln er ab le

gr ou

ps .V

ul ne ra bl e gr ou

p ha

d m or e ac tiv

at io n of

do rs om

ed ia lP

FC an

d le ss ac tiv

at io n

of V S an

d ex te nd

ed am

yg da la .I nc re as ed

do rs om

ed ia lp re -fr on

ta la ct iv at io n an

d de cr ea se d

V S an

d am

yg da la ac tiv

at io n co rr el at ed

po si tiv el y

w ith

ex te rn al iz in g be ha

vi or s

(C on

ti nu

es )

1939

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

H oe fe r et al .

20 14

Cr os s- se ct io na

l/ pr o sp ec tiv e

co ho

rt st ud

M R I/ vo lu m et ri c

da ta

N on

e LD

H ;

Ta qm

an ge no

ty pi ng

as sa y; W A IS

II I;

BV M T;

A M N A RT

7 m on

th s

Sm ok in g al co ho

l- de pe nd

en t:

m ea n 49

.6 SD

(9 )

N on

-s m ok in g

al co ho

l-d ep en de nt :

m ea n 53

.6 (1 0. 5)

N on

- sm

ok in g co nt ro ls :

m ea n 45

.6 SD

(9 .9 )

n m al e = 14

4, n fe m al e = 12

(s m ok in g al co ho

l- de pe nd

en t

↔ no

n- sm

ok in g

al co ho

l-d ep en de nt

↔ no

n- sm

ok in g

co nt ro ls )

A D ha

d sm

al le r hi pp oc am

pi th an

he al th y

co nt ro ls at

al lt im

e- po in ts .H

ip po ca m pa l

vo lu m e at

1 m on

th of ab st in en ce

co rr el at ed

w ith

lo w er

vi su os pa tia

lf un

ct io n

Sm ok in g st at us

di d no

t in fl ue nc e vo lu m e or

re co ve ry .B

D N F Va

lh om

oz yg ot es

ha d

hi pp oc am

pa lv ol um

e in cr ea se s ov er

7 m on

th s

of ab st in en ce ,a nd

Va lh

om oz yg ot es

ha d

si gn

ifi ca nt ly la rg er

hi pp oc am

pi th an

M et

ca rr ie rs at

7 m on

th s of ab st in en ce

Jo hn

so n-

G re en e et al .

19 97

Pi lo t st ud

y PE

T N on

e N eu ro ps yc h ol og ic al

ba tt er y

U p to

32 m on

th s

A D m ea n:

48 .6

SD (1 0. 2)

n m al e = 6 (A D

lo ng

itu di na

l) A bs tin

en t gr ou

p sh ow

ed pa rt ia lr ec ov er y of

IC M R gl c in

tw o of th re e di vi si on

s of th e fr on

ta l

lo be s an

d im

pr ov em

en t on

ne ur op sy ch ol og ic al

te st s of ge ne ra lc og ni tiv e an

d ex ec ut iv e

fu nc tio

ni ng

,w he re as

th e pa tie nt s w ho

re la ps ed

ha d fu rt he r de cl in es

in th es e ar ea s

K üh

n et al .

20 14

Cr os s- se ct io na

l/ pr os pe ct iv e

co ho

rt st ud

M R I/ vo lu m et ri c

da ta

N on

e LD

H 2 w ee ks

A D :m

ea n 42

.1 SD

(1 1. 6)

Co nt ro ls :m

ea n 40

.8 SD

(3 .4 )

n m al e = 53

, n fe m al e = 21

(A D de to xi fi ed

↔ he al th y co nt ro ls )

A D gr ou

p ha

d lo w er

CA 2 + 3 ba se lin

e vo lu m e

an d si gn

ifi ca nt

no rm

al iz at io n of gr ay

m at te r

vo lu m e 2 w ee ks

la te r. N eg at iv e co rr el at io n

be tw

ee n ba se lin

e CA

2 + 3 vo lu m e an

d al co ho

l co ns um

pt io n an

d al co ho

l-w ith

dr aw

al sy m pt om

s. A D pa tie nt s w ith

st ro ng

er w ith

dr aw

al sy m pt om

s di sp la ye d th e la rg es t vo lu m e in cr ea se

of CA

2 + 3

M on

et al .

20 11

Pr os pe ct iv e

co ho

rt st ud

y M R I/ vo lu m et ri c

da ta /

m at he m at ic al

pr ed ic tio

N on

e N on

e 22

2 da ys

A D :m

ea n 50

.7 SD

(1 1. 9)

n m al e = 13

, n fe m al e = 3

Th e da ta

pr ed ic te d fr om

th e fo rm

ul a w er e

ve ry

si m ila r to

th e ex pe ri m en ta lly

m ea su re d

da ta

fo r al ll ob es

an d fo r bo th

gr ay

an d w hi te

m at te r (in

tr ac la ss co rr el at io n co ef fi ci en ts ↔

0. 95

) M on

et al .

20 13

M R I/ vo lu m et ri c

da ta

N on

e LD

H ;

5 w ee ks

A D :m

ea n 50

.8 SD

(1 0. 6)

n m al e = 70

, n fe m al e = 9

VA L ho

m oz yg ot e in

A D gr ou

p re la te d to

gr ay

m at te r in cr ea se .V A L/ M ET

he te ro zy go te

(C on

ti nu

es )

1940 Katrin Charlet et al.

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

Cr os s- se ct io na

l/ pr o sp ec tiv e

co ho

rt st ud

Ta qm

an ge no

ty pi ng

as sa y; W A IS

II I

Co nt ro ls :m

ea n 47

.9 SD

(7 )

(A D de to xi fi ed /

lo ng

itu di na

l↔ LD

) as so ci at ed

w ith

w hi te

m at te r in cr ea se s. G ra y

m at te r vo lu m e in cr ea se s co rr el at ed

po si tiv el y

to ne ur oc og ni tiv e m ea su re

in cr ea se s

Pf ef fe rb au

m et al .1

99 5

Pr os pe ct iv e

co ho

rt st ud

y M R I/ vo lu m et ri c

da ta

N on

e N on

e U p to

12 m on

th s

A D :m

ea n 45

.0 SD

(1 0. 9)

Co nt ro ls :m

ea n 45

.3 SD

(1 4. 2)

n m al e = 11

6 (A D de to xi fi ed /

lo ng

itu di na

l ↔

co nt ro ls )

Fr om

(1 ) to

(2 ) sc an

,A D gr ou

p sh ow

ed de cl in es

in CS

F vo lu m es

of la te ra lv en tr ic le s

an d po st er io r co rt ic al su lc i, an

d an

in cr ea se

in an

te ri or

co rt ic al gr ay

m at te r

vo lu m e. Fr om

(2 ) to

(3 ) sc an

th ir d ve nt ri cu la r

vo lu m es

de cr ea se d in

th e ab st ai ne rs re la tiv e to

th e re la ps er s an

d co nt ro ls ;c or tic al w hi te

m at te r

vo lu m e de cr ea se d in

th e re la ps er s. In

th e

re la ps er s al co ho

lc on

su m pt io n pr ed ic te d la te r

vu ln er ab ili ty

to w hi te

m at te r vo lu m e de cl in e

an d th ir d ve nt ri cu la r en la rg em

en t w ith

re la ps e

Pf ef fe rb au

m et al .2

00 1

Cr os s- se ct io na

l M R I/ vo lu m et ri c

da ta

N on

e LD

H N on

e A D m al e: m ea n 43

.4 SD

(8 .4 ) A D

fe m al e: m ea n 41

.7 SD

(9 .5 )

Co nt ro ls m al e: m ea n

44 .6

SD (1 1. 4)

Co nt ro ls fe m al e:

m ea n4

2. 9

SD (1 3. 4)

n m al e = 92

, n fe m al e = 79

(A D de to xi fi ed

m al e/ fe m al e ↔

he al th y co nt ro ls

m al e/ fe m al e)

Le ss br ai n sh ri nk

ag e w as

fo un

d am

on g al co ho

lic w om

en th an

am on

g al co ho

lic m en

Pf ef fe rb au

m et al .2

01 4

Pr os pe ct iv e

co ho

rt st ud

y M R I/ D TI / TB

SS N on

e Se lf- re po rt ed

dr in ki ng

hi st or ie s

U p to

8 ye ar s

A D :m

ea n 44

.3 SD

(9 .2 )

Co nt ro ls :m

ea n

43 .0

SD (1 0. 1)

n m al e = 52

, n fe m al e = 51

FA of A D lo w er

th an

th at

of he al th y co nt ro ls .

R el ap si ng

A D sh ow

ed co nt in ue d w or se ni ng

, w he re as

ab st ai ni ng

A D sh ow

ed im

pr ov em

en t

in fi be r in te gr ity .F A tr aj ec to ri es

of re la ps er s

ex hi bi te d fa st er

ag in g re la tiv e to

co nt ro ls ,

w he re as

th e tr aj ec to ri es

of ab st ai ne rs sh ow

ed im

pr ov em

en t to w ar ds

no rm

al ity

(C on

ti nu

es )

1941

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

R ui z et al .

20 13

Cr os s- se ct io na

l M R I/ vo lu m et ri c

da ta

N on

e N on

e A D :m

ea n 53

.9 SD

(1 1)

Co nt ro ls :m

ea n 53

.9 SD

(1 2. 4)

n = 44

(A D

de to xi fi ed

m al e/ fe m al e ↔

he al th y co nt ro ls

m al e/ fe m al e)

Fe m al e A D sh ow

ed st ro ng

er po si tiv e as so ci at io ns

be tw

ee n so br ie ty

du ra tio

n an

d w hi te

m at te r

vo lu m e th an

m en

in fi rs t ye ar

of ab st in en ce .

M en

sh ow

ed hi s as so ci at io n m or e so

th an

w om

en af te r 1 ye ar

of ab st in en ce

Sa m et ie t al .

20 11

Cr os s- se ct io na

l M R I/ vo lu m et ri c

da ta

N on

e C- D IS

N on

e Lo ng

-t er m

ab st in en t

A D :m

ea n 46

.6 SD

(6 .7 )

Co nt ro ls :m

ea n 45

.6 SD

(6 .5 )

n m al e = 53

, n fe m al e = 47

(lo ng

-t er m

ab st in en t

A D ↔

he al th y

co nt ro ls )

M in im

al di ffe re nc es

in su bc or tic al st ru ct ur e

vo lu m es

be tw

ee n lo ng

- te rm

ab st in en t A D an

d co nt ro ls .I n A D gr ou

p di ffe re nc es

in vo lu m e

as so ci at ed

w ith

cu rr en t or

lif e- tim

e ps yc hi at ri c di ag no

si s

Se go bi n et al .

20 14

Cr os s- se ct io na

l/ pr os pe ct iv e

co ho

rt st ud

M R I/ te ns or -b as ed

m or ph

om et ry

N on

e N on

e 6 m on

th s

A D

pa tie nt s: m ea n 44

.4 SD

(6 .0 7)

Co nt ro ls :m

ea n 46

.7 SD

(4 .2 5)

n m al e = 37

, n fe m al e = 2

(A D ↔

he al th y

co nt ro ls ;

A D /l on

gi tu di na

R ed uc ed

th al am

us vo lu m e as so ci at ed

w ith

re la ps e. R ec ov er y of ce re be llu

m ,s tr ia tu m

an d

ci ng

ul at e gy ru s

ev en

in A D pa tie nt s w ith

m od er at e al co ho

l in ta ke

bu t

ne g. Co

rr el at ed

to am

ou nt

of al co ho

lc on

su m ed

ov er

6 m on

th s in

A D gr ou

p va n Ei jk et al .

20 13

Cr os s- se ct io na

l/ pr os pe ct iv e

co ho

rt st ud

M R I/ V BM

N on

e N on

e 2 w ee ks

A D :m

ea n 47

.0 SD

(1 0. 1)

Co nt ro ls :m

ea n 45

.3 SD

(1 1. 9)

n m al e = 82

, n fe m al e = 22

(A D de to xi fi ed /

lo ng

itu di na

l ↔

he al th y

co nt ro ls )

G ra y m at te r vo lu m e (c in gu

la te

gy ru s, m id dl e

an d pr e- ce nt ra lp re -fr on

ta lg yr i, ce re be llu

m ,

in su la ) sm

al le r in

A D co m pa re d w ith

co nt ro l

gr ou

p at

ba se lin

e. Si gn

ifi ca nt

re co ve ry

af te r

2 w ee ks

of ab st in en ce

Vo lk ow

et al .

19 94

Pr os pe ct iv e

co ho

rt st ud

y PE

T N on

e N on

e U p to

2 m on

th s

A D :m

ea n 41

.0 SD

(8 )

Co nt ro ls :m

ea n 38

.4 SD

(3 )

n m al e = 20

(A D de to xi fi ed /

lo ng

itu di na

l ↔

he al th y

co nt ro ls )

M et ab ol is m

in cr ea se d pr ed om

in an

tly in

fi rs t

30 da ys

of ab st in en ce .I nc re as es

m ai nl y in

pr e- fr on

ta lr eg io ns .M

et ab ol is m

co rr el at ed

ne ga tiv el y to

al co ho

lu se

(C on

ti nu

es )

1942 Katrin Charlet et al.

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

Vo lk ow

et al .

20 06

Cr os s- se ct io na

l PE

T N on

e M ul ti- di m en si on

al pe rs on

al ity

qu es tio

nn ai re

N on

e FH

P: m ea n

24 SD (3 )

FH N :m

ea n

26 SD (4 )

n m al e = 28

n fe m al e = 2

FH P gr ou

p ha

d si gn

ifi ca nt ly hi gh

er m ea su re s

of D 2 re ce pt or

av ai la bi lit y in

ca ud

at e an

d V S.

FH P su bj ec ts ha

d lo w er

m et ab ol is m

in hi pp oc am

pa lg yr us ,t em

po ra lp ol e an

d ce re be llu

m .M

et ab ol is m

in pr e- fr on

ta lc or te x

in cr ea se d in

FH P. Po

si tiv e co rr el at io n be tw

ee n

st ri at al D 2 re ce pt or

av ai la bi lit y an

d m et ab ol is m

in O FC

,v en tr al ci ng

ul at e gy ru s an

d PF

C. D 2

re ce pt or

an d m et ab ol is m

in le ft O FC

w as

co rr el at ed

po si tiv el y to

po si tiv e em

ot io na

lit y

W an

g et al .

20 16

Pr os pe ct iv e

co ho

rt st ud

y M R I/ vo lu m et ri c

da ta

(C T, SA

)

N on

e N on

e 14

da ys

A D :m

ea n

47 .0 2

SD (1 0)

Co nt ro ls :m

ea n

46 .6 5

SD (1 2. 37

)

n m al e = 47

n fe m al e = 12

(A D ↔

co nt ro ls )

Lo w er

su bc or tic al vo lu m es

in A D in

pu ta m en ,

N A ,a m yg da la an

d hi pp oc am

pu s. N o su bc or tic al

vo lu m e re ga in

at FU

.C or tic al vo lu m e re co ve ry

dr iv en

by an

in cr ea se

in CT

.M or e CT

re du

ct io n

an d re co ve ry

in su lc ic om

pa re d to

gy ri

W ei la nd

et al .2

01 2

Cr os s- se ct io na

l fM

R I/ PP

I N -b ac k ta sk

Ca lif or ni a Ch

ild Q -S or t

N on

e m ea n 20

.2 SD

(1 .2 )

n m al e = 43

, n fe m al e = 24

(p ar en ta l

al co ho

lis m

↔ no

pa re nt al al co ho

lis m )

H ig h re si lie nc e: co rr el at ed

ne ga tiv el y to

ST N ,

pa lli du

m ac tiv

at io n;

co rr el at ed

po si tiv el y to

lo w er

le ve ls of su bs ta nc e us e, fe w er

al co ho

l pr ob le m s an

d be tt er

w or ki ng

m em

or y

pe rf or m an

ce Ya

u et al .

20 12

Cr os s- se ct io na

l fM

R I

M ID

ta sk

D ri nk

in g an

d dr ug

hi st or y

N on

e CO

A s:

m ea n 20

.1 2

SD (1 .2 )

Co nt ro l: m ea n 20

.1 SD

(1 .3 )

n m al e = 24

, n fe m al e = 16

(C O A s ↔

co nt ro ls )

R es ili en ce

re la te d to

re du

ce d ve nt ra ls tr ia tu m

ac tiv

at io n in

CO A s

Za ki ni ae iz

et al .2

01 6

Pr os pe ct iv e

co ho

rt st ud

y fM

R I/ IC D

In di vi du

al iz ed

im ag er y

pa ra di gm

N on

e 90

da ys

St ud

y 1

A D :m

ea n 37

.7 3

SD (1 .1 6)

St ud

y 1

n m al e = 35

, n fe m al e = 10

A D sh ow

ed de cr ea se d ci ng

ul at e co nn

ec tiv

ity in

re sp on

se s to

al co ho

la nd

st re ss cu es

co m pa re d

to ne ut ra lc ue s. W ea ke r co nn

ec tiv

ity in

A CC

(C on

ti nu

es )

1943

Ta bl e 1.

(C on

tin ue d)

M et ho d

St ud y

St ud y de si gn

N eu ro im ag in g

Pa ra di gm

O th er te st s

Fo llo w -u p

pe ri od

A ge

St ud y sa m pl e

M ai n fi nd in gs

St ud

y 2

A D :m

ea n 35

.9 7

SE (0 .0 8)

Co nt ro ls :m

ea n

34 .4 7

SE (1 .5 5)

St ud

y 2

n m al e = 43

n fe m al e = 17

an d M CC

du ri ng

ne ut ra lc ue

ex po su re

re la te d

to lo ng

er ab st in en ce .P

CC co nn

ec tiv

ity du

ri ng

al co ho

lc ue s co m pa re d to

st re ss cu e co nd

iti on

s co rr el at ed

po si tiv el y to

lo ng

er tim

e to

re la ps e

Ci ng

ul at e co nn

ec tiv

ity si gn

ifi ca nt ly di ffe re nt

be tw

ee n gr ou

ps .A

D sh ow

ed re du

ce d ci ng

ul at e

co nn

ec tiv

ity du

ri ng

al co ho

la nd

st re ss cu es

an d in cr ea se d ci ng

ul at e co nn

ec tiv

ity du

ri ng

ne ut ra lc ue s. A D m or e si m ila r to

co nt ro ls in

ci ng

ul at e co nn

ec tiv

ity ha

d lo ng

er ab st in en ce

an d be tt er

re co ve ry

M R I=

m ag ne tic

re so na

nc e im

ag in g; D TI

= di ffu

si on

te ns or

im ag in g; A D = al co ho

l-d ep en de nt ;S D = st an

da rd

de vi at io n; ↔

= ve rs us ;F A = fr ac tio

na la ni so tr op y; R D = ra di al di ffu

si vi ty ;P ET

= po si tr on

em is si on

to m og ra ph

y; FH

P = fa m ily

hi st or y

po si tiv e; FH

N = fa m ily

hi st or y ne ga tiv e; BP

N D = bi nd

in g po te nt ia l; FD

G = 18

F- fl uo

ro de ox yg lu co se ;f M R I=

fu nc tio

na lm

ag ne tic

re so na

nc e im

ag in g; PP

I= ps yc ho

ph ys io lo gi ca li nt er ac tio

n an

al ys is ;P

FC = pr e- fr on

ta lc or te x; ES PA

D = Eu

ro pe an

Sc ho

ol Su

rv ey

Pr oj ec to

n A lc oh

ol an

d ot he r D ru gs ;S D Q = st re ng

th s an

d di ffi cu lti es

qu es tio

nn ai re ;D

A W BA

= de ve lo pm

en ta

nd w el lb ei ng

as se ss m en

t, LE Q = lif e ev en ts qu

es tio

nn ai re ;A

CC = an

te ri or

ci ng

ul at e co rt ex ;D

BM = de fo rm

at io n- ba se d

m or ph

om et ry ;L D H = lif e- tim

e dr in ki ng

hi st or y; LD

= lig ht

dr in ke rs ;O

FC = or bi to fr on

ta lc or te x; D LP

FC = do rs ol at er al pr e- fr on

ta lc or te x; SU

D = su bs ta nc e us e di so rd er ;F EF

= fr on

ta le ye

fi el d; SE F = su pp le m en ta ry

ey e fi el d; G M

= gr ay

m at te r;

W M

= w hi te

m at te r; sA

D = sm

ok in g al co ho

l-d ep en de nt ;n

sA D = no

n- sm

ok in g al co ho

l-d ep en de nt ;B

V TM

= br ie fv

is uo

sp at ia lm

em or y te st ;M

TL = m ed ia lt em

po ra ll ob e; Y SR

= yo ut h se lf- re po rt ;C

OA = ch ild re n of

al co ho

lic s; V S = ve nt ra l

st ri at um

;p os .=

po si tiv el y; W A IS II I=

W ec hs le rA

du lt In te lli ge nc e Sc al e; A M N A RT

= A m er ic an

N at io na

lA du

lt R ea di ng

Te st ;B D N F = br ai n- de ri ve d ne ur ot ro pi c fa ct or ;I CM

R G LC

= re gi on

al ce re br al gl uc os e up

ta ke ;n eg .=

ne ga tiv e; c- D IS = co m -

pu te ri ze d di ag no

st ic in te rv ie w

sc he du

le ;F

U = fo llo w -u p;

CT = co rt ic al

th ic kn

es s; ST

N = su bt ha

la m ic nu

cl eu s; M ID

= m on

et ar y in ce nt iv e de la y;

PC C = po st er io r ci ng

ul at e gy ru s; M CC

= m id -c in gu

la te

co rt ex ;I CD

= in tr in si c co nn

ec tiv

ity di st ri bu

tio n.

1944 Katrin Charlet et al.

observed in the resilient group. The vulnerable group showed more activation of dorsomedial pre-frontal cortex (PFC) and less activation of ventral striatum and extended amygdala. Increased dorsomedial PFC activation and de- creased subcortical activation were linked to greater exter- nalizing behavior [35].

Another study, by Charlet et al. [11], assessed brain re- sponses during a face-matching task to investigate implicit emotion processing among detoxified AD and healthy con- trols. Greater activation of anterior cingulate cortex (ACC) during the processing of aversive faces correlated with lon- ger subsequent abstinence and less subsequent binge drinking during the subsequent 6 months. This ACC re- sponse may indicate a possible resilience/recovery factor, presumably reflecting successful emotion regulation and error monitoring [12].

Taken together, findings derived from the fMRI studies indicate potentially important roles of basal ganglia and pre-frontal brain. While two of three studies in COAs point to an increased resilience associated with less task-elicited neural activation within the basal ganglia [36,37], those in AD patients showed that greater PFC engagement may underpin resilience against relapse in patients during early abstinence (cf. [10–12,33,38,41]).

Resilience and recovery markers detected by studies using PET

Despite the wealth of pre-clinical and clinical evidence about dopaminergic function in addiction [41–43], studies focusing on resilience and recovery in alcohol dependence are sparse [16,44–47].

Two 11C-raclopride PET studies measured D2/D3 do- pamine receptor availability in healthy young adults with either a positive (FHP) or a negative (FHN) family history of AD pre and post an amphetamine challenge. In both, unaffected FHP displayed a higher level of striatal D2 [46] and D2/D3 [44] dopamine receptor availability in striatal regions compared with FHN. Interestingly, while amphet- amine resulted in the expected increase in dopamine and positive subjective effects in FHN individuals, this was not found in FHP individuals [44]. Such results support the hy- pothesis that high D2 receptor availability may serve as a protective biomarker compensating for the higher inherited vulnerability ([46], p. 1004). Further, striatal D2 receptor availability in FHPwas also linked significantly to pre-frontal glucosemetabolismwhich, in turn, was asso- ciated positively with emotional positivity [46]. This sug- gests that dopaminergic modulation of cognitive control over emotional responses protects against developing alco- hol addiction.

In AD, PET studies have demonstrated lower levels of DA receptor availability and DA release compared with healthy controls (e.g. [16,43].

Two early studies used PET to assess recovery of brain glucose metabolism during abstinence in AD. One reported a significant increase in brain glucose metabolism predom- inantly within 16–30 days, especially in frontal brain re- gions, whereas low metabolism persisted in the basal ganglia [47]. Another study showed that the four patients who remained abstinent compared with two who relapsed showed partial recovery in brain metabolismwithin frontal cortex areas as well as significant improvement in general cognitive and executive functioning [45].

In sum, PET studies concentrating on recovery and re- silience in alcohol dependence are sparse, but suggest that differences in dopaminergic function may result in vulner- ability or resilience depending on the genetic background of an individual. While high D2/D3 receptor availability may serve as protective non-alcoholic FHP, low D2 receptor availability may render individuals more vulnerable to al- cohol abuse. Further, similarly to fMRI studies, normaliza- tion in metabolism is associated with abstinence.

Resilience and recovery markers detected by sMRI

We found 21 relevant studies investigating changes in brain structure during abstinence ([21,48–67], cf. Table 1).

Smaller gray matter (GM) and white matter (WM) vol- umes have been found throughout the brain and were as- sociated with relapse within 6 months after detoxification [65]. Interestingly, increases in brain volumes were seen even in those patients with moderate alcohol consumption (< 10 g of pure alcohol per day) after detoxification. This indicates beneficial effects of reduced alcohol consumption in AD who are not ready or able to become abstinent [65]. Some brain areas appeared to recover faster, such as the cingulate gyrus in comparison to the fusiform gyrus, which led the authors to propose that recovery in one area trig- gers recovery in other connected areas.

Along with ventricular volume recovery, significant volume increases in subcortical GM were observed mainly within the first month of abstinence in AD compared with the following 7.5 months of abstinence [53,62]. Indeed, frontal GM normalized to control level, although total cor- tical and regional GM volumes (e.g. parietal, temporal, tha- lamic) remained lower after 7.5 months of abstinence [53]. Similarly, Gazdzinski et al. [54] showed that recovery of brain tissue was six times faster during the first 3 weeks of abstinence than during the subsequent 12months of ab- stinence [54]. Brain volume gain was more prominent in heavier drinkers with less tissue at baseline [54]. Partial re- covery of cortical thickness was also found after only 2 weeks of sobriety with full normalization seen in medial OFC and rostral ACC. Regeneration of sulci was more pro- nounced here in all affected brain areas than in gyri [67]. Another study showed significant normalization of

1945

hippocampal GM volume within the first 2 weeks of absti- nence in AD, especially in those with greater withdrawal severity at baseline [21].

Other studies have also found smaller tissue volumes associated with greater previous alcohol intake [21,51], e.g. in frontal and temporal cortices [51].

Mon et al. [58] modelled longitudinal brain structure changes mathematically in AD patients, and found that in those with greater GM/WM atrophy at baseline (usually directly after detoxification), greater dynamic neuroplastic changes occurred within the first month of cessation of alcohol intake [58]. Using deformation-based morphome- try, two studies by Cardenas et al. reported that 1week after detoxification patients had smaller frontal and temporal GM and WM volume, but those who remained abstinent regained WM and GM tissue in cortical and subcortical regions after 6–9 months [51]. Apart from structural GM reductions in AD patients relative to controls, subsequent abstainers and relapsers showed different patterns of GM volume loss [50]. In particular, future relapsers showed reduced GM in bilateral OFC in relation to abstainers, which might indicate conservation of GM in this region to benefit recovery in AD patients [50]. In terms of subcortical regions, Deshmukh et al. [52] also discovered regional volume atrophy in caudate, putamen and nucleus accumbens in AD men abstinent for approximately 204 days compared to healthy controls, with greater volume deficits in the nucleus accumbens seen in themore recently abstinent patients [52].

Interestingly, some studies did not find significant WM differences between AD and controls [53,67], although WM volume gain has been detected with abstinence. DTI is probably more sensitive to WM change than structural MRI, as detailed architecture of white matter tissue can be analyzed by visualizing molecule diffusion patterns [48,55]. For example, a longitudinal study utilizing DTI reported improvement of white matter fiber tract coherence and myelin integrity in the corpus callosum of recently detoxified AD during 1 year of abstinence [48]. Notably, these WM indices in AD no longer differed from controls [48]. However, there was no relationship between theseWMchanges with normalization of workingmemory function in the AD [48]. Similarly, normalization of whole brain fiber tract integrity was observed in abstainers with multiple scans during the course of 8 years, while relapsers showed accelerated microstructural damage of the white matter, i.e. faster aging [61].

Potential modulators

One potential mechanism underlying recovery could be related to genotype, such as has been shown for brain- derived neurotropic factor (BDNF Val66Met (rs6265) polymorphism), a promyelination neurotropin which

serves as a neurobiological marker of neuronal growth and maintenance [59,68]. AD who are homozygous for Val demonstrated frontal, parietal and thalamic GM increase during the first 5 weeks of abstinence and greater hippocampal volume recovery during 7 months of sobriety [57]. This was not seen in Val/Met heterozygotes, although both Val/Val and Val/Met carriers showed tissue gains in temporal GM [59]. Interestingly, Mon et al. [59] observed significant increases in frontal WM volumes only in Val/Met heterozygotes but not in Val homozygotes, as well as subcortical volume decreases in caudate GM in Val but not Met carriers. Furthermore, Hoefer et al. found hippocampal volume changes to be associated with improvements in visuospatial memory performance only in BDNF Val homozygotes (but not in Met carriers) [57].

Structural atrophy and recoverymay also vary between genders. Here, a recent study observed that the duration and quantity of heavy drinking was related significantly to WM reductions that differed regionally between male and female AD [63]. Furthermore, stronger positive associ- ations between duration of abstinence and WM volume were seen in women, while men showed this association more so than women after 1 year of sobriety [63], confirming gender-specific recovery processes [60,69]. An- other gender-driven GM difference indicating heightened vulnerability to brain atrophy in women was observed by Sameti and coworkers [64]: long-term abstinent alcohol- dependent women (mean = 6.3 years) displayed smaller nucleus accumbens volumes compared to healthy women and male controls. However, no significant gender effects have also been detected, such as in GM increases and cere- brospinal fluid (CSF) decreases in some brain areas ob- served within the first 2 weeks of alcohol abstinence [66].

Comorbid nicotine dependence is also important to con- sider, because up to 80% of AD smoke [70,71] and is itself neurotoxic [55,56]. Evidence is, however, inconsistent. While non-smoking AD revealed faster microstructural recovery (i.e. in frontal, temporal, parietal and occipital lobes) compared with smoking alcohol-dependent patients, faster macrostructural increases in frontal and temporal WM volume were seen in smokers only, with no changes of metabolic concentrations in both groups [55]. Contrary to those WM volume findings, smoking AD were found to show less recoverywith increasing age, especially in frontal (and total cortical) GM volume. Moreover, beneficial effects regarding processing speed were associated with the found morphological GM increases, but again in non-smoking AD only [53]. Another study could not support anyof these smoking-dependent recovery findings [57].

Studying neurobiological underpinning of resilience and its predication of problematic alcohol use, a recent European adolescent study by Burt et al., including 1870 teens (average age = 14.56 years), identified elevated GM volumes in pre-frontal areas (BA 11, 10, 6) in resilient

1946 Katrin Charlet et al.

adolescents (high competence in academic, social and emotional domains despite experiencing adverse life-time events in the past) compared with other peers, which also correlated negatively with problematic drinking, thus potentially preventing those teens from future AD development by the PFC regulating behavior with protective executive control [49].

In summary, structural neuroimaging studies demon- strate beneficial plasticity effects throughout the brain of AD during short-, medium- and long-term abstinence, even when patients lower their alcohol consumption to only amoderate level. However, recovery of neuronal tissue (GM versus WM or sulci versus gyri) appears to recover variably across regions (frontal areas first in early abstinence) and at different time rates.

DISCUSSION AND FUTURE AVENUES FOR RESEARCH

Neuroimaging research has been key in shedding light upon possible dysfunctional domains and affected brain regions in AD and their potential of recovery after alcohol cessation (or reduction). In summary, lower dopamine receptor availability as shown in PET studies related to craving in AD patients [16] which, in turn, has been associated with relapse [10,15]. Moreover, fMRI studies have linked deficient reward and emotion processing to negative treatment outcomes, while structural MRI studies have shown that conserved PFC morphology in particular is linked to resilience and abstinence in AD patients. Altogether, investigations of morphology identified specific factors that influenced these observed brain recovery processes and should be considered in future studies on brain recovery in AD, e.g. genotype-dependent neuronal (re)growth [57,59], gender-specific neural recovery effects [52,60,63,64,66,69], additional smoking influences [56,57,72] or adolescent alcohol abuse [49].

Overall, the reviewed research suggests that volumetric brain tissue recovery processes follow non-linear trajecto- ries, suggesting that faster reconstitution of regionally spe- cific brain areas during early abstinence might trigger the recovery of associated regions consecutively. Consistent with these results, additional life-time and current psychi- atric diagnoses (such as anxiety disorders, including post- traumatic stress disorder or externalizing disorder) have been identified as critical factors that interfere with mor- phometric brain recovery in alcohol dependence [64].

However, in reviewing these studies, onemust be aware of some methodological diversity when trying to compare or summarize the existing study findings. Here, in addition to replication studies, meta-analyses that weigh findings by their effect sizes could be employed to preserve false positive findings or small effect-sized results from overestimation. Also, the usage of different self-report instruments (without

verification by collateral information) to assess measures of alcohol consumption (e.g. life-time drinking amount, onset and pattern of drinking) should be regarded in light of a potential bias towards socially desirable answers, which might cause underestimation of reported drinking due to embarrassment (e.g. [10–12]).

Future studies that aim at systematic investigation of factors that mediate recovery and resilience are the focus of some system-oriented approaches (cf. [73]). On a func- tional level, different domains play a crucial role for the development and maintenance of addictive disorders and thus are important factors for recovery, on one hand, and resilience on the other hand: executive functions, including inhibitory control andworkingmemory, reward processing as well as processing of emotional stimuli, are potential tar- gets for diagnosis, prognosis and therapy [10–12].

However, until now most imaging studies in this field of research have been cross-sectional, and there is a clear necessity for longitudinal studies into the characterization of disease trajectories, progression rates andmarkers for re- covery and resilience to inform treatment options. Indeed, cohort studies as carried out by the IMAGEN consortium (e.g. [74]) can shed light on potential future research direc- tions; here, researchers from multiple European countries aim to identify neuronal predictors for developing addictive disorders as well as potential targets for AD prevention ap- proaches. Additional application of machine learning algo- rithms may further help to generate models of current and future alcohol misuse by incorporating the assessed brain processes and structures, personality as well as cognitive factors, environmental conditions and finally genetic markers [74]. Regarding the identification of intermediate phenotypes of resilience, more studies are clearly needed, as this field of neurobiological research is somewhat unex- plored. Here, investigations of individuals with andwithout heightened genetic or environmental risk forADareneeded to help disentangling resilience markers from vulnerability risk factors. Recent studies also introduced epigenetic mechanisms in AD, adding valuable information about modulating processes to the genotype–phenotype interac- tion [75]. Those investigations shoulduse appropriate study designs, such as comparisons of (i) adolescent/young adult COAswith versus without AD on their own or (ii) adult AD patients versus adult individuals without AD, but with a positive family history of AD (e.g. first-degree relatives of AD patients) versus healthy individuals without familiar or own AD (as in the recent ongoing prospective cohort study, e:Med SysMedAlcoholism [73]), respectively. Clearly, findings testing neurobiological traits of vulnerability to AD (cf. [76–78]) may give rise to new hypotheses and research questions, but caution is warranted that vulnerability markers are not simply the opposite of resilience. Rather, vulnerability demonstrates conditions and aberrations which exist before AD and may facilitate developing AD

1947

but are not only caused by, for example, neurotoxic alcohol effects. Conversely, resilience refers to factors that promote good treatment outcome despite negative effects of long- term alcohol intake on neural structure and function.

Further, future research should not only continue to strengthen knowledge concerning recovery processes and resilience markers (in high-risk groups without alcohol dependence as well as in already affected AD) but should also address whether they can be translated to various drugs of abuse in terms of general markers or can be char- acterized specifically for different substance classes.

Declaration of interests

None.

Acknowledgements

This work has been supported by the German Ministry of Education and Research (BMBF; 01ZX1311E and 01ZX1311D/e:Med-program alcohol addiction, Spanagel et al. 2013; and in part by 01EE1406A) and the German Research Foundation (DFG; CH 1936/1–1; FOR 16/17; HE2597 13–1/2, 14–1/2, 15–1/2, Excellence Cluster Exc 257).

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Supporting Information

Additional supporting information may be found online in the Supporting Information section at the end of the article.

Appendix S1 Overview of the systematic literature re- search: imaging resilience and recovery in alcohol depen- dence.

1950 Katrin Charlet et al.

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