Behavioural Brain Research 327 (2017) 121–132

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Behavioural Brain Research

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Research report

Resting state brain connectivity patterns before eventual relapse into

cocaine abuse
M. Berlingeri a,b,∗ , D. Losasso d , A. Girolo c , E. Cozzolino d , T. Masullo d , M. Scotto e ,
M. Sberna g , G. Bottini e,f,b , E. Paulesu c,h,∗∗
a
DISTUM, Department of Humanistic Studies, University of Urbino Carlo Bo, Urbino, Italy
b
NeuroMi, Milan Center for Neuroscience, Italy
c
Psychology Department, University of Milano-Bicocca, Milano, Italy
d
SERT 1, Dependence Department, ASL Milano, Milano, Italy
e
Center for Cognitive Neuropsychology, Niguarda Cà Granda Hospital, Milano, Italy
f
Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
g
Neuroradiology Department, Niguarda Cà Granda Hospital, Milano, Italy
h
fMRI Unit, I.R.C.C.S. Galeazzi, Orthopedic Institute, Milano, Italy

h i g h l i g h t s

• Addicted patients had a reduction of the connectivity between NAs and DMN.
• The worst the controlled behaviour, the higher the NA − oPFC connectivity.
• The worst the controlled behaviour, the lower the NAs − dPFC connectivity.
• The dynamics in the relapsed patients resemble a push-pull model.

a r t i c l e i n f o a b s t r a c t

Article history: According to recent theories, drug addicted patients suffer of an impaired response inhibition and salience
Received 15 February 2016 attribution (I-RISA) together with a perturbed connectivity between the nuclei accumbens (NAcs) and the
Received in revised form orbito-prefrontal (oPFC) and dorsal prefrontal (dPFC) cortices, brain regions associated with motivation
27 December 2016
and cognitive control. To empirically test these assumptions, we evaluated the (neuro)psychological
Accepted 1 January 2017
Available online 3 January 2017
trait and the functional organization of the resting state brain networks associated with the NAcs in 18
former cocaine abusers (FCAs), while being in drug abstinence since 5 months. The psychological data
were grouped into three empirical variables related with emotion regulation, emotion awareness and
Keywords:
Cocaine strategic and controlled behaviour.
fMRI Comparison of the resting state patterns between the entire sample of FCAs and 19 controls revealed a
Nucleus accumbens reduction of functional connectivity between the NAcs and the dPFC and enhanced connectivity between
I-RISA the NAcs and the dorsal-striatum. In the 8 FCAs who relapsed into cocaine use after 3 months, the level
Functional connectivity of functional connectivity between the NAcs and dPFC was lower than the functional connectivity esti-
Resting state fMRI mated in the group of patients that did not relapsed. Finally, in the entire sample of FCAs, the higher the
connectivity between the NAc and the oPFC the lower was the level of strategic and controlled behaviour.
Taken together, these results are compatible with models of the interactions between the NAcs, the dor-
sal striatum and frontal cortices in the I-RISA syndrome, showing that such interactions are particularly
perturbed in patients at greater risk of relapse into cocaine abuse.
© 2017 Elsevier B.V. All rights reserved.

Abbreviations: BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BIS, Barratt Impulsiveness Scale; DERS, Difficulties in Emotion Regulation; DA, DERS, subscale
awareness; DG, DERS, subscale goals; DI, DERS, subscale impulsivity; DoA, days of abstinence; dPFC, dorsal prefrontal cortex; EA, emotional awareness; ER, emotion regulation;
FCAs, former cocaine abusers; GAF, global assessment functioning; IGT, Iowa Gambling Task; I-RISA, impaired response inhibition and salience attribution; NAc, nucleus
accumbens; oPFC, orbito-prefrontal cortex; PCA, Principal Component Analysis; SCB, strategic and controlled behaviour; TAS, Toronto Alexithymia Scale; VOI, volume of
interest; zFC, z transformed functional connectivity maps.
∗ Corresponding author at: Dipartimento di Studi Umanistici, DISTUM, Università degli Studi di Urbino Carlo Bo Via Bramante, 17-61029 Urbino (PU).
∗∗ Corresponding author at: Dipartimento di Psicologia, Università degli studi di Milano-Bicocca Piazza dell’ateneo nuovo 1, edificio U6, 20126, Milano (MI), Italy.
E-mail addresses: manuela.berlingeri@uniurb.it (M. Berlingeri), eraldo.paulesu@unimib.it (E. Paulesu).

http://dx.doi.org/10.1016/j.bbr.2017.01.002
0166-4328/© 2017 Elsevier B.V. All rights reserved.
122 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132
1. Introduction
1.1. Theoretical background
Drug addiction, and in particular cocaine addiction, is a
widespread phenomenon in Europe, no social class or cultural
group being immune: according to recent surveys from the Euro-
pean Monitoring Centre for Drugs and Drug Addiction,1 on average,
2.8% of the general population has taken cocaine at least once, with
peaks for the UK and Spain (9.9% and 8.8%). These results are even
more worrying if one considers the data regarding successful reha-
bilitations: most of the cocaine abusers need a long-term period
of rehabilitation and those patients who succeed often do so only
after many attempts, while many do not succeed at all [56,48,20].
There are several models of drug addiction and the ensuing
behaviour. For example, Everitt and Robbins [21] suggest that the
addicts’ compulsive behaviour could be seen as “a maladaptive
stimulus-response habit in which the ultimate goal of the behaviour
has been devalued so that the behaviour is not directly under the
control of the goal” [21,pag 1485]. Accordingly, the initial impulse
associated with drug-craving would develop in a compulsive drug
assumption. At the neural level, it is established that cocaine
reinforces the connectivity within the dopaminergic system [73];
the limbic system (the ventral striatum, the amygdala, the hip-
pocampal structures, the anterior cingulate (ACC) and the insula)
and the dorsal striatum are important targets of the dopaminer-
gic projections [64,35,21,60]. All these structures are functionally
connected with different portions of the prefrontal cortex: here
dopamine-responsive cells contribute to emotional/behavioural
control, executive functions (such as action planning monitoring
and attentional control) and memory encoding [52,36]. A key-
region within the limbic system and key target of cocaine is the
nucleus accumbens (NAc; [23]). The NAc, and its perturbed con-
nectivity, is also at the heart of Baler and Volkow’s model [6]
of addiction. They propose that chronic addiction leads to the
dysfunction of the systems that mediate goal-directed behaviour.
According to the model, (see also Fig. 1b in [6]) addicted patients do
not have adequate control of their emotions, of their impulses and
their behaviour, in conjunction with a strong connectivity between
the NAc and both orbito-frontal (oPFC) and dorsal prefrontal cortex
(dPFC); cocaine-related hyper-stimulation of the NAc would cause a
decreased inhibitory control of dPFC over oPFC, leaving behavioural
planning, monitoring and decision-making processes at the mercy
of the impulses. In this respect, they resemble to patients with an
Obsessive Compulsive Disorder [42]. While a detailed discussion
of the empirical evidence behind Baler and Volkow’s model [6] is
beyond the scope of our paper, it is worth emphasizing that the
model makes some testable hypotheses that proved useful here.
It has been hypothesised that this clinical/behavioural pattern
may represent a specific clinical entity: the “impaired response inhi-
bition and salience attribution” (I-RISA) syndrome [30]. The I-RISA
syndrome hypothesis is supported by task-related neuroimaging
findings showing that drug addicted patients have a significant
increment of the neural activity in the oPFC and in anterior cingu-
late cortex when drug-craving is elicited by an external stimulation
[70,26]. Interestingly, these two brain regions have been associated
with the expression of obsessive-compulsive disorders [49,44] and
with pathological worry [58], and are part of the neural network
described in influential models of drug addiction [21,60,6].
On the other hand, habit reinforcement is seen as another key
aspect of chronic drug-addiction: according to Everitt and Robbins
[22], the transition from drug-related behaviours to hardwired −
1
Permanent link to the EMCDDA data: www.emcdda.europa.eu/data/
2014#displayTable:GPS-22.
drug independent − habits, or stereotyped repetitive behavioural
patterns, has a biological counterpart in an altered connectivity
between the ventral and the dorsal striatum whereby the dorsal
striatum takes a more prominent role in guiding behaviour.
These models are in part supported by the results of resting
state PET studies [77] and functional activation studies in human
addicts [69,35]. PET studies have shown a reduced metabolism
in oPFC, a key region of the reward system. Most of the activa-
tion studies in chronic addiction were based on tasks designed
to elicit drug craving [72] or drug-related memories [18,74] and
tasks that elicited emotion processing [4] and controlled behaviour
[25]. Taken together, these studies document an abnormal meso-
corticolimbic functioning [28].
It remains to be seen whether these abnormalities, originally
described during active tasks, are also present in a resting-state
condition and to what extent these correlate with behaviours or
with the tendency to relapse after drug abstinence. Our experi-
ment was designed to fill this gap and to further bind the cognitive
aspects of the I-RISA syndrome with its neurofunctional counter-
parts (i.e. the Baler and Volkow’s model [6]). To this aim we adopted
a resting state functional connectivity analysis of brain patterns and
we tested their correlations with behavioural and cognitive pro-
files. In particular we concentrated on patients in a condition of
abstinence from recent drug intake, but at risk of relapse into drug
abuse. We mapped the connectivity of a region of great interest for
addiction, namely the NAcs of both sides.
There are advantages in resting state fMRI studies when study-
ing patients [16], the first and foremost being the ease and speed
whereby the data are acquired, a factor that contributes to accu-
mulate sizeable patients populations. The second advantage is that
one can target a region of interest and its connectivity without the
concern on whether that region will be particularly active in a given
paradigm. This is particularly relevant for regions like the ventral
striatum (the initial target of our functional connectivity analysis)
for which it is not established how reproducible are, at a single
subject level, activations in a conventional task driven protocol.
We therefore reasoned that using a functional connectivity
approach at rest we might have been able to address questions
like the following ones more easily. The first one is obvious given
our methodological approach (1) is it possible to detect a cocaine-
related dysfunction of the NAc by default (i.e. in the absence of a
task)? The following ones are less obvious: (2) is such dysregula-
tion detectable also after a long abstinence from the drug? (3) Are
these abnormalities associated with significant changes of emotion
regulation, of goal-directed behaviour and “impulse control”? (4) Is
it possible to link these cognitive and neurofunctional aspects with
the risk of relapse into addiction?
1.2. Aims of the study
To evaluate the foundations of recent neuroscientific models of
cocaine addiction, we measured the resting state fMRI functional
connectivity in former cocaine abusers (FCAs) while in an absti-
nence state since 5 months, on average, and in healthy controls. The
neurofunctional changes associated with cocaine addiction were
then correlated with measures of goal-directed behaviour and emo-
tion control.
Moreover, to make an initial attempt to isolate a possible predic-
tive marker of the risk of relapse for FCAs, we collected follow-up
information 3 months after the fMRI scan. We then compared
patients that had relapsed into addiction with those who were still
in a remission state.
This effort led to the identification of behavioural and functional
anatomical patterns associated with the I-RISA syndrome, patterns
that correlated with the eventual relapse into addiction. As the
reader will see, the present results are best accommodated by a
 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132 123

Fig. 1. Correlation matrix between observed variables.

The figure illustrates that correlation matrix between the 7 selected variables does not correspond to an identity matrix being therefore suited for data reduction. The lower
triangular matrix shows the Pearson correlation coefficients between the 7 observed variables. In the upper triangular matrix we report a graphical representation of the
correlation coefficient, the greater the radius of the circles, the stronger the correlations. The colour-legend is displayed in the colour-bar on the right. The correlation plot
was designed by means of the “corrplot library” available in R.
DG = DERS subscale Goals, DI = DERS subscale Impulsivity, BIS = Barrat Implusivity Scale, TAS = Toronto Alessitimia Scale, DA = DERS subscale Awareness, DoA = days of Absti-
nence, IGT = Iowa Gambling Task.

modified model of the interaction between the NAc and the dorsal
and orbital subdivision of prefrontal cortex.
2. Materials and methods
2.1. Participants
Eighteen former cocaine abusers (FCA; 18 male; mean
age = 39.28 ± 9.1; education level = 10.11 ± 3.2) and 19 healthy
controls (13 male and 6 female; mean age = 33.05 ± 9.11; educa-
tion level = 15 ± 4.01) participated in the study; all participants
were right-handed as assessed with the Oldfield scale [54]. All
the FCAs had a DSM IV-TR [3] diagnosis of cocaine depen-
dence; none reported the abuse of other drugs; at the time of
fMRI scanning, all the FCAs were in a condition of abstinence
(mean = 141 days ± 172.6). All the FCA patients were interviewed
also 3 months after the neuropsychological and MRI assessment to
evaluate the presence of possible relapses, these self-reports were
corroborated by means of urine tox-screen. Four of the eighteen
patients were light smokers [61], only 8 patients out of 18 were
defined light drinkers according to Abel et al. [1] at the clinical
interview.
Eight patients relapsed into cocaine abuse after 3 months from
their fMRI scan.
On the other hand, none of the healthy controls reported a his-
tory of substance abuse or addiction, with the exception of nicotine
intake as caused by moderate smoking (less then 15 cigarettes/day;
[61]). None of the participants had diabetes or any other relevant
disease; in particular, none reported a history of head injury, of
neurological or of psychiatric disorders.
All the participants gave their written consent to the experi-
ment (according to the Declaration of Helsinki 1991); the study
was approved by the Ethics Committee of the Niguarda Ca’ Granda
Hospital of Milan and by the Ethics Committee of the ASL Milano.
2.2. Neuropsychological and psychological assessment
The FCAs’ cognitive profile was assessed using a neuropsycho-
logical battery investigating non-verbal reasoning (Raven Coloured
Progressive Matrices; [59]), mental flexibility (Wisconsin Card Sort-
ing Test; [11]), inhibitory control (Stroop test; [66]), problem
solving (Tower of London; [63]), decision making (IOWA gambling
test; [7]), cognitive estimation skills [19], sustained and divided
attention (Trail Making Test; [27]), verbal and spatial short-term
memory (Digit Span task and Corsi’s Block Tapping task; [55]),
controlled word retrieval (Phonemic and Semantic Verbal Fluency
Tasks; [53]).
The psychological profile was assessed by means of the fol-
lowing clinical scales: the Barratt Impulsiveness Scale (BIS-11;
[57]), the Difficulties in Emotion Regulation Scale (DERS; [32]),
the Toronto Alexithymia Scale (TAS-20; [5]), the Beck Depression
Inventory (BDI; [9]), the Beck Anxiety Inventory [8] and the DSM
124 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132
IV-TR Axis V through the Global Assessment of Functioning Scale,
which evaluates the level of the individual global psychiatric func-
tioning (GAF, APA, 2000).
2.3. Principal component analysis on
behavioural/neuropsychological data
Emotion regulation and goal-directed behaviour are considered
to be particularly impaired in cocaine abusers [31]. To extract
cumulative empirical measures of these two aspects from our
large set of behavioural variables, we selected the 7 variables that,
according to our hypotheses and to the specific construct validity
of each psychometric instrument, can be associated with our two
constructs of interest: “Emotion Regulation” and “Goal-directed
Behaviour”. In particular, we selected 3 subscales from the DERS
(namely the sub-scales for awareness −DA-, goals −DG- and impulse
−DI), the scores obtained at the TAS-20, at the BIS-11, at the Iowa
Gambling Task (IGT) and finally the days of abstinence (DoA) before
the fMRI scan. These variables were entered in a Principal Compo-
nent Analysis (PCA) that was run with the software SPSS 21. As a
first step, the correlation matrix between observed variables was
explored and tested for not being an identity matrix by means of the
Bartlett’s test. Second, the component with an eigenvalue greater
than 1 were extracted. Moreover, in order to obtain independent
latent variables that can be interpreted more easily, a VARIMAX
rotation of the axes was applied. For each FCA patient the latent
scores were obtained by means of a regression analysis based on
the rotated PCA matrix. As it is common practice, the interpretation
of the functional significance of each component, was based on a
qualitative assessment of the relative loadings from each observed
variable. A tentative functional label was then attached to each
component latent variable on the basis of the relative loadings.
2.4. Functional connectivity analyses
2.4.1. Acquisition parameters
MRI scans were performed by using a General Electrics
1.5 T Signa scanner equipped with gradient-echo echo-planar
(Flip angle 90◦ , TE = 60msec, TR = 3000msec, FOV = 280 × 210 mm;
matrix = 96 × 64). Each volume consisted of 35 contiguous oblique
images (thickness = 4 mm, gap = 0 mm) acquired along the AC-PC
plane. A total amount of 200 volumes were acquired (acquisi-
tion time = 10 min). During the fMRI scanning, all subjects were
instructed to keep their eyes closed, not to move and to try
not to think about anything in particular. Moreover, for each
participant, a T1-weighted MP-RAGE (3D Magnetisation Pre-
pared Rapid Gradient-Echo) scan was acquired (Flip angle = 20◦ ,
TE = 2.92 ms, TR = 9.16 ms, acquisition matrix: 256 × 256; thick-
ness = 1 mm, interslice gap = 0 mm, and voxel size = 1 × 1 × 1 mm).
The volumetric MRI scans included 145 slices acquired on oblique
sections parallel to the AC-PC line to cover the entire brain volume.
2.4.2. Preprocessing and subject-by-subject analyses
The resting-state functional connectivity analyses were made
using the toolbox DPARSF [75] − advanced edition (DPARSF-A;
http://rfmri.org/DPARSF) and a seed-based approach. The seeds
were created as a spherical volume of interest (VOI) with a 5 mm
radius centred over the stereotactic coordinate reported in the
study by Cauda et al. [15] for the nuclei accumbens: ±12; 10;
−8. The VOIs were designed by means of the software MRIcron
(http://www.mccauslandcenter.sc.edu/mricro/mricron/) and then
converted into the NIFTI format to make them compatible with the
DPARSF-A software. The fMRI scans were realigned and the vol-
umetric T1 image was coregistered to the functional ones. Once
coregistered, the T1 image was passed to the unified segmenta-
tion algorithm to obtain the grey, white and cerebrospinal fluid
maps. At this stage, signal decomposition was applied. In par-
ticular, from the 200 fMRI volumes, we covaried out the effect
of global signal, of the rigid body transformation (6 parameters),
of white matter and cerebrospinal fluid signals. The fMRI images
were then normalized to the MNI EPI template and they were
rescaled to obtain isotropic voxels of 3 × 3 × 3 mm. The normal-
ized images were finally smoothed with a Gaussian FWHM filter
of 5 × 5 × 5 mm. After the preprocessing steps, the signal was fil-
tered to isolate the low frequency fluctuations within the range of
0.01-0.08 Hz, a frequency range of physiological importance that
should reflect spontaneous neuronal activity [12,50]. For each par-
ticipant, the mean time course was extracted from each seed of
interest and correlated, on a voxel-by-voxel basis, with the fluctua-
tions in the entire brain volume to create subject-specific functional
connectivity (FC) maps. The correlation coefficient represented in
the subject-specific functional connectivity maps were finally z-
transformed by means of the Fisher’s r-to-z transform function
(from now on zFC maps). Thus, as a final result we obtained a zFC
map for each seed of interest, for each participant (74 zFC maps in
total considering both seeds).
2.4.3. Comparisons between normal controls and FCAs
The 74 zFC maps were entered into 2 × 2 full factorial design
(2 seeds, 2 groups) and the seed of interest was modelled as a
within group factor. From this experimental design (hence called
Full Factorial 1; FF1), we extracted the following effects of interest:
• across group commonalities: i.e. the brain regions that show a
similar level of functional connectivity with the NAcs in the two
groups; this effect was computed as a full conjunction effect;
• group-by-seed interaction effect;
• functional connectivity augmentations in FCAs;
• functional connectivity reductions in FCAs.
2.4.4. Multiple regression analysis between behavioural scores
and zFC maps in FCAs
A voxel-by-voxel multiple regression analysis on the patients’
zFC maps was computed. Here, the NAcs zFC maps were entered
as dependent variables, while the latent factors extracted from the
PCA of the behavioural/neuropsychological data were entered as
regressors.
2.4.5. Comparison between relapsed and stable FCAs and the
impact of behavioural variables
In a further independent full factorial analysis (hence called Full
Factorial 2; FF2), we assessed the zFC maps differences between
relapsed and stable patients; these sub-groups were defined on
the basis of the data collected during a clinical interview 3 months
after the fMRI scan. As before, we assessed the between-group dif-
ferences together with group-by-side interaction effects.
The between-group differences were further assessed to evalu-
ate whether the latent factors extracted from the PCA can moderate
these effects. To this aim, the mean percentage signal change
was extracted from the brain regions that showed a significant
between-group difference by means of the Mars-Bar toolbox [13].
These data were used as a dependent variable in a random intercept
general linear model in which the second level interaction effects
between either group, or seed, and each latent factor were used as
predictors. The random effect was modelled according to the factor
“cerebral hemisphere” (i.e. to the within-subject factor).
2.4.6. Statistical thresholds
In all our analyses, given the functional connectivity approach
adopted, we were more interested in finding distributed rather
than highly focal patterns. Accordingly, we found the best compro-
mise between sensitivity and specificity as follows: an uncorrected
 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132 125

Table 1
Clinical psychological and neuropsychological profile of FCAs.

Clinical Psychological tests Mean Sd FCAs impaired Neuropsychological tests Mean Sd FCAs impaired

BIS-11 71.44 ±14.78 4 Raven Black and White Progressive Matrices 34.83 ±7.5 1
BIS-11 − attentional 17.72 ±5.04 – Wisconsin Card Sorting test/fall sett 1.11 ±1.1 1
BIS-11 − motor 24.61 ±6.53 6 Wisconsin Card Sorting test/global 49.28 ±34.6 2
BIS-11 − non planning 29.78 ±6.61 7 Wisconsin Card Sorting test/perseverations 12.94 ±10.8 1
DERS 81.94 ±27.79 5 STROOP/time 15.07 ±8.8 1
DERS − non acceptance 12.11 ±6.18 4 STROOP/errors 0.97 ±1.5 2
DERS − goals 12.67 ±5.69 4 Tower of London test 17.54 ±2.4 –
DERS − impulse 12.17 ±7.15 4 IOWA gambling test −7.53 ±16.2 5
DERS − awareness 19.17 ± 5.52 10 Cognitive estimation test 16.61 ±4.6 11
DERS − strategies 14.11 ±5.8 2 Trail Making test A 31.83 ±14.6 –
DERS − clarity 11.06 ±4.4 2 Trail Making test B 80.89 ±46.7 2
GAF 59.78 ±7.34 – Digit Span test 5.61 ±1.29 1
TAS-20 48.89 ±15.36 8 Phonemic fluency 36.39 ±10.54 –
BDI 12.50 ±12.09 5 Semantic fluency 50.05 ±9.18 –
BAI 13.39 ±15.81 4

BIS-11 = Barratt Impulsiveness Scale; DERS = Difficulties in Emotion Regulation Scale; GAF = Global Assessment of Functioning. TAS-20 = Toronto Alexithymia Scale; BDI = Beck
Depression Inventory; BAI = Beck Anxiety Inventory.

voxel-wise threshold of p < 0.01 was combined with a cluster-wise Table 2

Principal components analysis: matrix of the component loads after varimax
threshold of p < 0.001 as computed by SPM8. This preliminary pro-
rotation.
cedure allowed us to identify clusters that were in most cases
significant for their spatial extent also after a gaussian-theory First Second Third
component component component
inspired correction for multiple comparisons: these clusters proved
(ER) (EA) (SCB)
significant up to a p < 0.001 FWE corrected threshold. In addition,
in the tables we also point to the regional effects that survived the DERS awareness 0.681 −0.356
DERS goals 0.941
FWE correction at a voxel level.
DERS impulse 0.903
TAS-20 0.564 0.658
BIS-11 0.763 −0.369
3. Results Iowa Gambling Task 0.971
Days of abstinence −0.823
3.1. Clinical psychological and neuropsychological tests

Table 1 shows the average performance at the clinical psycho-

logical and neuropsychological tests, together with the number of
patients that showed a significant impairment for each test.
Neuropsychological deficits, when seen on the entire population
of FCAs, were very occasional and did not reveal a clear-cut pattern:
yet only 2 patients scored within norms in all tests.
3.1.1. Clinical psychological tests
Five patients obtained a pathological score in one scale only,
while the remaining 7 patients showed more than one patholog-
ical score (see Table 1 for more details). The tests in which there
were more subjects affected were the BIS-11 non-planning subscale,
the DERS awareness scale, and the TAS-20 scale for alexithymia. On
the other hand, 6 patients out of 18 obtained a psycho-affective
cognitive profile completely in the normal range.
3.1.2. Neuropsychological tests
All patients but 3 did show some neuropsychological impair-
ment in tests designed to assess the integrity of the frontal lobe.
Eight patients had an isolated pathological performance while 7
patients obtained a score below the normal threshold in more than
one test. In any event, these deficits again did not reveal a clear
pattern. The Cognitive Estimates Test and the Iowa Gambling Task
(11/18 and 5/18 patients below threshold respectively) were the
tests with more frequent pathological performance.
ponents can be considered a reliable linear combination of the
selected observed variables.2
From the principal component analysis on the behavioural data,
3 components, that explained the 78.7% of the total variance, were
extracted. The component matrix (after the VARIMAX rotation),
i.e. a matrix that includes the components loadings, is reported in
Table 2.
The first factor was mainly associated with the loading of the
DERS, subscale goals (DG), of the DERS, subscale impulsivity (DI),
of the TAS-20 and of the BIS-11; given these loadings, we defined
this latent factor as the Emotion Regulation (ER) factor. All variables
have a positive load in this component to imply that the higher the
factor score, the more dysfunctional the behavioural trait.
The second factor was mainly associated with the subscale
awareness of the DERS (DA), with the TAS-20 and with the days of
abstinence (DoA) before the fMRI scan. Here the first two variables
had a positive load, while the third was negatively correlated. We
interpreted this factor as a measure of Emotional Awareness (EA).
Here again, the higher the latent-score, the worse the psychological
profile.
Finally, the third factor was represented by the DERS, subscale
awareness (DA), by the BIS-11 and by the score obtained at the Iowa
Gambling Task (IGT). This component was interpreted as a measure
of the ability to have a Strategic and Controlled Behaviour (SCB). The
first two variables had a negative load, while the third a positive

3.1.3. Principal component analysis on

behavioural/neuropsychological data
The correlation matrix between the observed variables is
reported in Fig. 1. As clearly shown from the results of the Bartlett’s
test (␹2 (21) = 49.21, p < .001), this matrix is significantly different
from an identity matrix, as a consequence, the extracted com-
2
There is a popular belief that PCA should be used only when the number of sub-
jects is exceedingly higher than the number of variables. However, there are strong
reasons to prefer a quantitative assessment of the data as we did here, in particular
if the aim is to reduce data complexity and to avoid the problem of multicollinearity
[38]. Indeed Bartlett’s test on the correlation matrix was highly significant to justify
the reduction of the data into linear combinations of them.
126 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132
one, to imply that the higher was the component score, the higher
was the level of strategic and controlled behaviour.
To make the interpretation of the results easier, the latent scores
of the first and second components were multiplied by “-1” to make
them compatible with the latent scores extracted from the SCB.
After this manipulation, the higher the latent score, the better the
level of emotional awareness and emotional regulation.
3.1.4. Comparison of the relapsed and the non-relapsed patients
None of the (neuro)psychological measures was sensitive
enough to tease apart the 2 groups as defined by the eventual
relapse into abuse at the 3 months follow-up. We found only a
significant difference in the days of drug abstinence before the
fMRI scan (relapsed: median = 23, interquartile range = 105; non-
relapsed: median = 106, interquartile range = 406; Mann-Whitney
U test: Z = −2.04, p=0.04).
3.2. Functional connectivity results
3.2.1. Full factorial design 1: group (healthy controls vs FCAs)
−by- side (NAcleft vs NAcright )
The patterns of functional connectivity of the left and right NAc
were very similar. In particular, we could find a significant laterality
effect (e.g. left NAc > right NAc) around the two seeds only. This
means that the FC of the left NAc was higher than FC of the right
NAc only in its neighbourhood and vice versa. Moreover, there was
not a significant group by seed-side interaction effect. Accordingly,
all subsequent effects were based on the functional connectivity
maps of the two NAcs lumped together.
FCAs and controls showed a distributed pattern of shared func-
tional connectivity: the NAcs were significantly associated with the
ventral and orbital PFC, with the cingulate cortex, with the insular
cortex and with the basal nuclei bilaterally (see Table 3).
However, FCAs showed a significant reduction of functional con-
nectivity between the NAcs and part of the right dPFC, the cortices
around the rolandic sulcus, the lateral parietal associative regions,
the retrosplenial cortices bilaterally (see Table 3). On the contrary
from the linear t-contrast FCAs > healthy controls only a significant
enhancement of the functional connectivity between the NAcs and
the surrounding basal ganglia regions emerged, in particular in the
dorsal striatum (see Table 3).
3.2.2. Voxel wise multiple regression analysis
To explore the relationship between behavioural and functional
connectivity dysregulations in FCA patients, we run two voxel wise
multiple regression analyses. Here the latent factors extracted from
the principal component analysis on the behavioural data were
entered as independent variables, while the right and the left NAc
zFC maps were entered as dependent variables.
We found a significant negative effect of the SCB component on
the level of functional connectivity between the right NAc and the
right orbital PFC (oPFC; plot in Fig. 2), the right insula, the right
superior temporal pole, the right caudate nucleus and the left cere-
bellum (Table 3) whereby the worse the Strategic and Controlled
Behaviour (SCB), the higher the functional connectivity (Fig. 2, plot
on the bottom). A similar effect was found also in the left hemi-
sphere (Table 3) when assessing the level of functional connectivity
of the left NAc.
3.2.3. Full factorial design 2: sub- group (Non-relapsed vs
Relapsed) −by- side (NAcleft vs NAcright )
Also in this case, the patterns of functional connectivity of the
two NAcs were highly similar with significant laterality effects
within the seeds themselves only. Accordingly, the between sub-
groups differences were based on the functional connectivity maps
of the two NAcs lumped together. In particular, we found a signif-
icant further reduction of functional connectivity for the relapsed
patients in the lateral dorsal PFC and in part of the medial dorsal PFC
(from the medial part of the superior frontal gyrus to the anterior
portion of the Cingulate cortex; Table 3). On the contrary, a signif-
icant increment of the functional connectivity between the NAcs
and the ventral parietal regions was found in the relapsed patients
(Table 3).
A further analysis showed that the functional connectivity
reduction between the NAc and the dorsal prefrontal cortices
(dPFC) in the relapsed patients was moderated by the level of
strategic and controlled behaviour whereby the lower the strategic
controlled behaviour, the lower the connectivity. At the technical
level, this was demonstrated by means of a random intercept model
analysis which revealed a significant interaction between the group
(relapsed versus non-relapsed) and the SCB factor (F(1,26) = 7.54;
p < 0.05–Bonferroni corrected). The effect was bilateral with no by-
side interaction effect. The results of this analysis are represented
in Fig. 3 (plot on the top left). The significant group-by-SCB inter-
action effect suggests that the correlation between the FC in the
dPFC and the SCB is significant in the relapsed patients only (see
the scatterplot on the upper-left panel in Fig. 3).
On the other hand, the same analysis on the emotional aware-
ness component proved only marginally significant (F(1,26) = 5.28;
p = 0.03 not corrected).
Finally, we evaluated, in the two groups separately, the cor-
relation between the functional connectivity level extracted from
the dPFC and the functional connectivity extracted from the oPFC
of both hemispheres. While in the stable patients the two level
of functional connectivity predicted by the SCB did not correlate
(r(20) = −0.17; p = 0.47), in the relapsed sub-group we found a sig-
nificant negative correlation between the SCB effects recorded in
the oPFC and in the dPFC (r(20) = −0.58; p = 0.02; Fig. 3, plot on the
top right). This pattern of results suggests that the higher the level
of SCB (i.e. the better the subjects are in terms of cognitive con-
trol), the lower the functional connectivity between the NAcs and
the oPFC, on the one hand, and the higher the level of functional
connectivity between the NAcs and the dPFC, on the other hand.
4. Discussion
Cocaine addicted patients show a progressive loss of self-
generated/goal-directed behaviours and enhanced automatic-
stereotyped sensory-driven responses [30,31,21,60] with patho-
logically enhanced habits. Our results expand in novel ways
previous evidence.
We start the discussion of our findings by reviewing the
behavioural profile of our patients and its consistency with the
concept of the I-RISA syndrome; we then continue by address-
ing our functional connectivity patterns and their correlation with
specific behavioural aspects of FCA patients. Finally, as our results
are somewhat at variance with the one predicted outcome from
Baler and Volkow [6] model, to accommodate the functional con-
nectivity patterns observed, we sketch a modified push-pull model
of the interaction of the NAc with the oPFC and dPFC, with particular
reference to the problem of relapse into addiction.
4.1. Behavioural patterns
All our patients were under psychological or social support and
in a condition of abstinence from the drug since 5 months on aver-
age; accordingly, any cognitive deficit was not due to the temporary
effect of a recent drug assumption. Their clinical and neuropsy-
chological pattern was fairly typical: 15 out of 18 showed at least
one deficit in a neuropsychological assessment designed to test
 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132 127

Table 3
Results of the resting state fMRI analyses.
Brain Regions x y z Z score x y z Z score
Left Hemisphere Right Hemisphere
A. Full Factorial design 1 (FF1): group (HCs vs FCAs) -by- side (NAleft vs NAright )
FC Commonalities
Middle Frontal gyrus −30 45 15 3.4
Inferior Frontal gyrus. pars orbitalis 33 30 −6 4.4
Superior Frontal gyrus. pars orbitalis −21 42 −12 3.3 15 36 −15 4.1
−15 15 −15 6.5# 15 36 −21 3.7
Middle Frontal gyrus. pars orbitalis 12 42 −6 4.6
Anterior Cingulum −3 33 24 3.4 6 36 3 4.9#
−9 39 3 5.3# 9 39 0 4.6
Insula −30 24 −3 4.1 42 15 −9 3.7
−39 12 −6 3.9 36 33 9 3.2
Middle Cingulum −3 27 36 3.5 3 24 33 3.7
Caudate −9 12 −9 6.4# 9 12 −9 7.3#
−6 9 −12 6.4# 12 12 0 6.8#
Putamen −15 15 −3 6.1# 18 15 −9 7.3***#
−18 6 −9 5.0#
Pallidum −12 9 3 6.3#
Amygdala −27 −6 −12 3.4
Thalamus −3 −6 −6 4.8#
FCAs’ FC Reductions
Middle Frontal gyrus 45 12 42 2.8
Precentral gyrus −45 −3 30 4.0*** 39 3 48 3.5***
−45 3 48 3.1 48 −6 54 3.3
Rolandic opercular gyrus −48 −21 15 3.4 60 −9 15 3.1
Postcentral gyrus −45 −33 54 3.7 60 0 21 3.1
−33 −42 66 3.9 27 −39 72 3.1
Superior Parietal gyrus −21 −57 54 3.3 24 −48 72 3.7***
−21 −48 72 3.6 33 −51 63 3.7
Inferior Parietal gyrus −30 −42 48 3.1
−51 −27 48 3.3
Supramarginal gyrus 66 −18 33 2.6
Precuneus −15 −54 75 3.5 12 −45 48 2.8
Cuneus −9 −84 18 3.4 0 −78 21 3.8*
−6 −81 39 3 18 −78 27 3.1
Superior Occipital gyrus −12 −75 24 3 21 −81 21 2.8
−15 −84 12 3.3
Superior Temporal gyrus −51 −15 3 3
−42 −36 24 3.3
Middle Temporal gyrus −66 −21 −6 3.1 66 −15 6 2.7
−66 −12 −9 3.4 60 −27 21 2.8

FCAs’ FC Enhancements
Putamen −24 −9 9 3.4
−15 9 6 3.2
B. Voxel-wise multiple regression analysis
Negative correlation between the functional connectivity of the right NAc and SCB
Superior Frontal gyrus. pars orbitalis 24 39 −12 2.1
Middle Frontal gyrus. pars orbitalis 30 51 −9 3.1
Rectus gyrus 9 18 −24 2.6
Inferior Frontal gyrus. pars orbitalis 30 21 −21 2.7
21 18 −18 3.6
Insula 42 27 −3 2.5
30 24 −12 3
Superior Temporal pole 45 12 −15 2.3
Caudate 15 12 −9 3.3
Cerebellum −27 −69 −42 3.8
−33 −78 −48 4.0*
Negative correlation between the functional connectivity of the left NAc and SCB
Inferior Frontal gyrus, pars orbitalis −30 21 −15 3.8
Inferior Frontal gyrus, pars triangularis −39 33 9 2.7
Superior Temporal pole −39 12 −21 3.5
−45 18 −18 3.2
Insula −27 12 −12 3.9**
−33 24 6 3
Amygdala −30 3 −18 2.8
Hippocampus −24 −6 −24 2.5
Putamen −24 15 0 3.5
C. Full Factorial design 2 (FF2): sub-groups (Non-relapsed vs Relapsed) -by- side (NAleft vs NAright )
Relapsed patients’ FC Reductions
Superior Frontal gyrus −21 54 21 2.9 24 60 6 3.2
15 42 30 3.4
Middle Frontal gyrus −24 54 9 3.6 36 54 9 2.7
30 57 3 3
Superior Frontal gyrus. medial −12 51 18 2.7 12 36 39 2.9
12 39 48 3.4
Anterior Cingulum −9 39 21 3.2 9 27 18 4.1***
Relapsed patients’ FC Enhancements
Postcentral gyrus −60 −15 36 5**#
−51 −27 54 4.5
Inferior Parietal lobule −54 −21 45 2.8
Coordinate in bold represent the local maxima of the cluster. ***: p < 0.001 FWE cluster-level corrected **: p < 0.01 FWE cluster-level corrected *: p < 0.05 FWE cluster-level
corrected #: p < 0.05 FWE voxel-level corrected.
128 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132

Fig. 2. Strategic and controlled behaviour and resting state functional connectivity of the nucleus accumbens with the orbitofrontal cortex in the whole sample of former
cocaine abusers.
For illustration purposes data from the right NAc and right oPFC are displayed. The altered functional connectivity between NAc and oPFC is negatively moderated by the
level of strategic and controlled behaviour (SCB) in the entire sample of FCA patients: the lower the level of SCB, the higher the level of functional connectivity between the
NAc and the oPFC. X-axis: SCB; Y-axis: predicted values of the linear model.

“frontal” executive functions, a proportion similar to that of pre-
vious reports [62,68,76]. Most of them (14 out of 18) continued
with the psychosocial treatment also 3 months after the MRI scan.
However, 8 patients relapsed into drug abuse, confirming how dif-
ficult it is to dismantle their reinforced and compulsive behaviour,
notwithstanding psychological and medical support (Marlatt et al.
1985; Carroll et al. 1994; De Lima et al., 2002). Interestingly, the
8 relapsed patients had been in an abstinence condition for a
shorter period (median: 23 days) than the non-relapsed patients
(median: 106 days). This result, with all the needed caution due
the dimensions of our samples, is compatible with the “incubation
of cocaine craving” phenomenon described in animal models [41]
suggesting that drug craving changes following an inverted posi-
tively skewed U-shaped curve. It is well possible that our relapsed
patients were still in the upper part of the “incubation” curve and
thus they were more sensitive to drug craving and behaviourally
relevant environmental stimuli, while the non-relapsed patients
(average abstinence for 3 months and an half) were in the lower
part of the craving curve. These phases of incubation of cocaine
craving are accompanied by complex subcortico-cortical neuro-
transmitter changes in animal models (recent reviews, for example,
in Xuan [39,45]).3 It is also worthy to note that the large proportion
of relapses may actually be related to the presence of executive
deficits, inducing lack of strategy and presence of perseverative
behaviour, and with behavioural impulsivity [36,2].
While no quantitative differences could be demonstrated
between relapsed and non-relapsed patients at the neuropsycho-
logical level, 6 out of the 8 relapsed FCA patients had at least one
deficit on tests of the executive functions (4 at the cognitive estima-
tion test, 1 at the Raven Matrices and 1 at the Iowa Gambling task,
at the Stroop test and at the Wisconsin Card Sorting Test); 5 out
of these 8 patients had a deficit at the DERS awareness sub-scale, 5
out of 8 at the BIS non-planning subscale. In addition, Fig. 3 (data
points on the low left side of the upper left plot) shows that a poor
3
Interestingly, our observations are similar to the ones of Kosten et al. [37] who
found the same proportion of relapses (8 out of 17) after a similarly delayed follow-
up. They also found that the relapsed patients had enhanced fMRI brain responses
for cocaine-related cues.
 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132 129

Fig. 3. Push-pull model of brain connectivity and behaviour in relapsing FCAs.

The top-left graph illustrates how the level of functional connectivity between NA and dPFC is significantly lower in relapsed patients. Moreover, in dPFC we found a positive
correlation between the strategic and controlled behaviour (SCB) and the level of functional connectivity with the NAcs for the relapsed patients only. Squares indicate data
points from the right NAc, filled circles indicate the effect from the left NAc.
The Top-right graph illustrates the push-pull model for relapsed patients. For the relapsed patients only, the level of functional connectivity between the NAcs and the dPFC
negatively correlated with the level of functional connectivity between the NAcs and the oPFC (r(20) = −0.58; p = 0.02). This means that the higher the connectivity in the oPFC,
the lower the connectivity in the dPFC and, in turn, the lower the level of strategic and control behaviour (see the top-left graph data for the relapsed FCAs).

strategic and controlled behaviour, together with a reduced func-
tional coupling of dPFC and NAc, is associated with a relapse into
addiction.
To summarize our clinical and behavioural observation, we
believe that our results fit with the cognitive/behavioural pattern
predicted by the I-RISA hypothesis.
4.2. Functional connectivity patterns: general
The aforementioned behavioural pattern did not have clear
functional anatomical counterparts to date, something offered
instead by our resting state functional connectivity results: these
provide evidence4 in support of the hypothesised link between the
I-RISA syndrome and the neurofunctional network described in the
Baler and Volkow’s model [6]. All FCAs, analysed as a single group,
showed a significant enhancement of the functional connectivity
between the NAcs and surrounding nuclei of the dorsal striatum
on the one hand, and by a significant reduction of the functional
connectivity between the right NA, the dPFC (in line with the dorso-
striatal network described in the paper by Haber [33]) and part
of the posterior regions of the default mode network (DMN). The
increment of functional connectivity at the level of the dorsal stria-
tum is compatible with Everitt and Robbins’s [21] model of chronic
addiction.
Abnormal connectivity within the DMN is also interesting. The
DMN has been associated with self-monitoring and introspective

4
Previous studies [43]that explored resting state functional connectivity in alterations and behavioural dysfunctions as they lack of a detailed psychologi-
addicted patients failed to report a direct connection between the neurofunctional cal/neuropsychological characterization.
130 M. Berlingeri et al. / Behavioural Brain Research 327 (2017) 121–132
thinking [10,46,14]. Moreover, in a recent resting state fMRI study,
[17] suggested that the dysfunction of the retrosplenial regions of
the DMN in drug addicted patients (as well as in adolescents with
conduct disorder) might represent the neurofunctional manifesta-
tion of the inability to successfully recollect past experiences and
memories5 ; this would reduce their decision making skills as well
as the ability to think about the consequences of actions (especially
for cases with negative outcomes).
Interestingly, the functional connectivity reduction between the
NAcs and the dPFC was in a set of stereotactic coordinates that are
almost identical to those reported in the study by Dalwani et al.
[17] on a sample of adolescents with either conduct, or drug-abuse
disorder.
We also found a significant dysregulation of the functional con-
nectivity between the NAcs and the oPFC. This effect was negatively
moderated by the SCB component: the worse the strategic and
controlled behaviour, the higher the level of functional connec-
tivity between the NA and the oPFC cortex (see plot in Fig. 2).
This latter finding is perfectly in line with Baler and Volkow’s pre-
dictions [6]: the augmented functional connectivity between the
NAcs and the oPFC may reflect a pathologically enhanced reward
system that goes in parallel with a deficit of strategic control. In
the same vein, our findings are compatible with the results of
the task-dependent fMRI study by Goldstein et al. [29] in which
drug-addicted patients showed a significant dysregulation of the
oPFC activity when submitted to a drug-related Stroop task dur-
ing an fMRI session. Interestingly, while the Goldstein’s patients
were in abstinence for a maximum of 96 days (mean = 12) and their
dysfunction was recorded in the presence of drug-related stim-
ulation, our patients, when seen as a single group, had been in
drug abstinence for 141 days on average, and they were scanned
in the absence of any external stimulation nor reference to the
drug. Thus, our results expand Goldstein’s findings by showing that
drug addiction may cause a profound and longer-lasting neurofunc-
tional change within the reward neural network. Our evidence is
also in line with other resting state fMRI studies on heroin-addicted
patients [43] to further support the idea that drug induced neuro-
functional alterations may share some mechanisms, independently
of the specific substance used [34,51].
4.3. Functional connectivity patterns: relapsed patients and a
modified “push-and pull model” of the connectivity of the nucleus
accumbens with frontal cortices in cocaine addiction
As discussed in the introduction, Baler and Volkow’s model [6]
of cortico-subcortical interactions in addiction has had the merit
of providing a set of testable hypotheses: according to the model,
addiction would be associated with “impaired information process-
ing within the reward network”.
However, the model predicts a similarly reinforced connectiv-
ity between the accumbens and both the oPFC and dPFC. On the
contrary, we rather found a reduction of functional connectivity
between the NAcs and the dPFC in FCA patients. This effect was
particularly significant in the relapsed patients: here the effect was
moderated by the SCB (see the plot on the top left in Fig. 3) to sug-
gest that the worse the level of strategic and controlled behaviour
at T0, the lower the level of functional connectivity between the
NAcs and the dPFC in patients that will relapse.
While we do not have information about a causal relationship in
the correlations between the nucleus accumbens and the two sub-
divisions of the frontal lobe, nor on the causal directions/signs of
5
The retrosplenial regions, together with the medial temporal structures, are
part of the neurofunctional system necessary to remember the past and imagine
the future by means of imagery-based simulation strategies [24].
these relationships, it is tempting to speculate on a push-pull mech-
anism whereby controlled behaviour, at least in relapsed patients,
becomes weaker because of the increased influence of the accum-
bens on the orbito-frontal cortex in parallel with a progressive
demise of a top-down control from dorsolateral prefrontal cortex
on behaviour.
This was also suggested by the inverse correlation between the
level of functional connectivity extracted from the dPFC and from
the oPFC (Fig. 3, plot on the top right) in the relapsed patients.
The dynamics envisaged by a push-pull model in the relapsed
patients, who were in abstinence from the drug since a shorter time,
is also compatible with the intuition that they may have been at the
top of the typical representation of the time course of drug craving,
an inverted positively skewed U shape ([41]; see also the previous
section of the discussion on the behavioural results).
However, it is impossible for us to tell whether the additional
abnormalities observed in the relapsed patients are part of the nat-
ural evolution of the craving post-abstinence experience that one
would observe in all FCAs, if these could have been studied at multi-
ple times after the beginning of the abstinence experience. In other
words, we cannot tell whether the two groups described come from
the same population, the relapsing ones being such because of an
unfavourable combination of the time-dependent status of their
neurobiology and environmental factors predisposing to relapse
[39]. Accordingly, it is safer for the time being to consider the two
groups as coming from the same population.6
In any event, in our small sample of patients a specific pat-
tern/mechanism seems to correlate with the chance of relapse into
drug abuse, or at least, it was specifically present only for those
who were about to relapse, suggesting that a revised push-and-pull
model of Baler and Volkow’s [6] may have some explanatory power,
at least for a specific time window of the abstinence experience.
Further studies using causal modelling of the fMRI data, much
larger samples of patients and multiple observations in a longi-
tudinal design may help to further test these hypotheses and to
develop a formal biomarker of relapse into abuse in cocaine addic-
tion. The ease of resting state fMRI studies, at least for the scanning
procedures, suggests that these hypotheses might be testable.
Acknowledgments
This study was supported by grants from the National Board of
Health for the national Project “High integration public and pri-
vate Units for the treatment and the rehabilitation of cocaine and
psycho-stimulant abusers” and by an integrative contribution from
ASL Milano.
Part of this study was presented at the European Workshop of
Cognitive Neuropsychology (Bressanone, Italy − 25–29 Jan 2016).
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